Multiplexed  pathlength resolved noninvasive analyzer apparatus with dynamic optical paths and method of use thereof

ABSTRACT

A noninvasive analyzer apparatus and method of use thereof is described comprising a near-infrared source, a detector, and a photon transport system configured to direct photons from the source to the detector via an analyzer-sample optical interface. The photon transport system includes a dynamically position light directing unit used to, within a measurement time period for a single analyte concentration determination, change any of: radius, energy, intensity, position, incident angle, solid angle, and/or depth of penetration of a beam of photons entering skin of a subject.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/493,283 filed Sep. 22, 2014, which:

-   -   is a continuation-in-part of U.S. patent application Ser. No.        13/963,925 filed Aug. 9, 2013;    -   is a continuation-in-part of U.S. patent application Ser. No.        13/963,933 filed Aug. 9, 2013, which is a continuation-in-part        of U.S. patent application Ser. No. 13/941,411 filed Jul. 12,        2013, which is a continuation-in-part of U.S. patent application        Ser. No. 13/941,389 filed Jul. 12, 2013, which is a        continuation-in-part of U.S. patent application Ser. No.        13/941,369 filed Jul. 12, 2013, which claims the benefit of:        -   U.S. provisional patent application No. 61/672,195 filed            Jul. 16, 2012;        -   U.S. provisional patent application No. 61/700,291 filed            Sep. 12, 2012; and        -   U.S. provisional patent application No. 61/700,294 filed            Sep. 12, 2012; and    -   claims the benefit of U.S. provisional patent application No.        61/885,365 filed Oct. 1, 2013,    -   all of which are incorporated herein in their entirety by this        reference thereto.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a near-infrared noninvasive analyzerusing a two-dimensional detector array.

DESCRIPTION OF THE RELATED ART

Patents and literature related to the current invention are summarizedherein.

Diabetes

Diabetes mellitus or diabetes is a chronic disease resulting in theimproper production and/or use of insulin, a hormone that facilitatesglucose uptake into cells. Diabetes is broadly categorized into fourforms grouped by glucose concentration state: hyperinsulinemia(hypoglycemia), normal physiology, impaired glucose tolerance, andhypoinsulinemia (hyperglycemia).

Diabetics have increased risk in three broad categories: cardiovascularheart disease, retinopathy, and/or neuropathy. Complications of diabetesinclude: heart disease, stroke, high blood pressure, kidney disease,nerve disease and related amputations, retinopathy, diabeticketoacidosis, skin conditions, gum disease, impotence, and/or fetalcomplications.

Diabetes is a common and increasingly prevalent disease. Currently,diabetes is a leading cause of death and disability worldwide. The WorldHealth Organization estimates that the number of people with diabeteswill grow to three hundred million by the year 2025.

Long term clinical studies show that the onset of diabetes relatedcomplications is significantly reduced through proper control of bloodglucose concentrations, The Diabetes Control and Complications TrialResearch Group, “The Effect of Intensive Treatment of Diabetes on theDevelopment and Progression of Long-Term Complications inInsulin-Dependent Diabetes Mellitus”, N. Eng. J. of Med., 1993, vol.329, pp. 977-986.

Skin

The structure of skin varies widely among individuals as well as betweendifferent skin sites on a single individual. The skin has layers,including: (1) a stratum corneum of flat, dehydrated, biologicallyinactive cell about 10 to 20 micrometers thick; (2) a stratifiedepidermis, of about 10 to 150 micrometers thickness, formed andcontinuously replenished by slow upward migration of keratinocyte cellsfrom the germinative basal layer of the epidermis; (3) an underlyingdermis of connective fibrous protein, such as collagen, and a bloodsupply, which form a layer of 0.5 to 4.0 millimeters in thickness withan average thickness of about 1.2 millimeters; and (4) a underlyingfatty subcutaneous layer or adipose tissue.

Fiber Optic Sample Bundle

Garside, J., et. al., “Fiber Optic Illumination and Detection Patterns,Shapes, and Locations for use in Spectroscopic Analysis”, U.S. Pat. No.6,411,373 (Jun. 25, 2002) describe software and algorithms to designfiber optic excitation and/or collection patterns in a sample probe.

Maruo, K., et. al., “Device for Non-Invasive Determination of GlucoseConcentration in Blood”, European patent application no. EP 0843986 B1(Mar. 24, 2004) describe the use of light projecting fiber optics in therange of 0.1 to 2 millimeters from light receiving fiber optics at thecontacted fiber optic bundle/sample interface.

Skin Thickness

Rennert, J., et. al., “Non-Invasive Method of Determining Skin Thicknessand Characterizing Layers of Skin Tissue In Vivo”, U.S. Pat. No.6,456,870 B1 (Sep. 24, 2002) describe the use of near-infraredabsorbance spectra to determine overall thickness of skin tissue andlayer-by-layer thickness of skin tissue.

Ruchti, T. L., et. al., “Classification System for Sex Determination andTissue Characterization”, U.S. Pat. No. 6,493,566 B1 (Dec. 10, 2002)describe the near-infrared tissue measurements to yield predictionsconsisting of gender and one or more of thickness of a dermis, collagencontent, and amount of subcutaneous fat.

Mattu, M., et. al., “Classification and Screening of Test SubjectsAccording to Optical Thickness of Skin”, U.S. Pat. No. 6,738,652 B2 (May18, 2004) describe the use of near-infrared reflectance measurements ofskin to determine the optical thickness of skin through analysis ofwater, fat, and protein marker bands.

Sample Probe/Tissue Contact

Abul-Haj, A., et. al., “Method and Apparatus for Noninvasive Targeting”,U.S. patent application no. US 2006/0217602 A1 (Sep. 28, 2006) describea sample probe interface method and apparatus for targeting a tissuedepth and/or pathlength that is used in conjunction with a noninvasiveanalyzer to control spectral variation.

Welch, J. M., et. al., “Method and Apparatus for Noninvasive Probe/SkinTissue Contact Sensing”, WIPO international publication no. WO2008/058014 A2 (May 15, 2008) describe a method and apparatus fordetermining proximity and/or contact of an optical probe with skintissue.

Problem Statement

What is needed is a noninvasive glucose concentration analyzer havingprecision and accuracy suitable for treatment of diabetes mellitus.

SUMMARY OF THE INVENTION

The invention comprises a noninvasive analyzer apparatus comprising adynamic optic system.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the present invention is derived byreferring to the detailed description and claims when considered inconnection with the Figures, wherein like reference numbers refer tosimilar items throughout the Figures.

FIG. 1 illustrates an analyzer;

FIG. 2 illustrates diffusely reflecting optical paths;

FIG. 3 illustrates probing tissue layers using a spatial distributionmethod;

FIG. 4 illustrates varying illumination zones relative to a detector;

FIG. 5 illustrates varying detection zones relative to an illuminator;

FIG. 6A illustrates an end view of a detector array and FIG. 6Billustrates a side view of the detector array;

FIGS. 7(A-E) illustrate a coupled source detector array system, FIG. 7A;a side illuminated/detector array system, FIG. 7B; a cornerilluminated/detector array system, FIG. 7C; a within array illuminationsystem, FIG. 7D; and an illuminated array/detector array system, FIG.7E;

FIG. 8A and FIG. 8B illustrate a first example of a multipletwo-dimensional detector array system and a second example of a multipletwo-dimensional detector array system, respectively;

FIG. 9A illustrates transmission spectra of longpass optical filters andFIG. 9B relates longpass filters to water absorbance;

FIG. 10 illustrates shortpass filter transmission spectra;

FIG. 11A illustrates bandpass filters relative to near-infrared spectralregions and FIG. 11B illustrates specialized bandpass filters;

FIG. 12 illustrates elements of a bimodal optical filter;

FIG. 13A and FIG. 13B illustrate a fat band filter and fat bandabsorbance, respectively;

FIG. 14A and FIG. 14B illustrate a glucose filter and glucoseabsorbance, respectively;

FIG. 15 illustrates a detector array with multiple filter array layers;

FIG. 16 illustrates a source array proximate a combined detector/filterarray;

FIG. 17 illustrates a source relative to multiple two-dimensionaldetector arrays;

FIG. 18A and FIG. 18B illustrate an illumination array relative tomultiple two-dimensional detector array types and rotatedtwo-dimensional detector arrays, respectively;

FIG. 19A and FIG. 19B illustrate a two-dimensional detector arrayrelative to an optic array in an expanded and assembled view,respectively;

FIG. 20A and FIG. 20B illustrate a detector array, longpass filterarray, shortpass filter array, and optic array in an exploded andassembled view, respectively;

FIG. 21A and FIG. 21B illustrate a detector array, longpass filterarray, shortpass filter array, and optic array in an exploded andassembled view, respectively;

FIGS. 22(A-D) illustrate temporal resolution gating, FIG. 22A;probabilistic optical paths for a first elapsed time, FIG. 22B;probabilistic optical paths for a second elapsed time, FIG. 22C; and atemporal distribution method, FIG. 22D;

FIGS. 23(A-C) illustrate a fiber optic bundle, FIG. 23A; a first examplesample interface end of the fiber optic bundle, FIG. 23B; and a secondexample sample interface end of the fiber optic bundle, FIG. 23C;

FIG. 24A illustrates a third example sample interface end of the fiberoptic bundle and FIG. 24B illustrates a mask;

FIG. 25 illustrates a mask selection wheel;

FIG. 26A illustrates a position selection optic; FIG. 26B illustratesthe position selection optic selecting position; FIG. 26C illustratessolid angle selection using the position selection optic; and FIG. 26Dillustrates radial control of incident light relative to a detectionzone;

FIG. 27A and FIG. 27B illustrate a pathlength resolved sample interfacefor a first subject and a second subject, respectively;

FIG. 28 provides a method of use of a data processing system; and

FIG. 29 provides a method of using a sample mapping phase and asubsequent subject specific data collection phase.

Elements and steps in the figures are illustrated for simplicity andclarity and have not necessarily been rendered according to anyparticular sequence. For example, steps that are performed concurrentlyor in a different order are illustrated in the figures to help improveunderstanding of embodiments of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention comprises a noninvasive analyzer apparatus and method ofuse thereof comprising a near-infrared source, a detector, and a photontransport system configured to direct photons from the source to thedetector via an analyzer-sample optical interface. The photon transportsystem includes a dynamically position light directing unit optionallyused to, within a measurement time period for a single analyteconcentration determination, change any of: radius, energy, intensity,position, incident angle, solid angle, and/or depth of penetration ofphotons entering skin of a subject.

In another embodiment, two optically stacked arrays of optical filtersas a portion of a noninvasive analyzer apparatus are used. The stackedarrays of optical filters are optionally configured to pass multipledistinct and/or overlapping wavelength ranges to an array of detectors,where the filter combination—detector array distance resolves diffuselyreflected/partially absorbed optical pathlengths through skin.

In yet another embodiment, a noninvasive analyzer apparatus and methodof use thereof using a plurality of two-dimensional near-infrareddetector arrays is described.

In still yet another embodiment, subsets of signals from one or moretwo-detector array are used to determine at least one of: sampledpathlengths, internal consistency, precision enhancement, skin type,photon path information, outlier analysis, and state of the subjecttested.

In a further embodiment, an apparatus and method of use thereof isdescribed using acquisition of noninvasive mapping spectra of skin andsubsequent optical/optical path reconfiguration for subsequent subjectspecific data collection.

For example, a near-infrared noninvasive analyzer is configured with afirst optical configuration used to map an individual and/or group ofindividuals through use of mapping spectra. The mapping spectra areanalyzed and used to reconfigure the optical setup of the analyzer to asecond optical configuration suited to the individual and/or group ofindividuals. Subsequently, collection of noninvasive spectra of theindividual and/or group of individuals is performed using the secondoptical configuration, which is preferably optimized to yield additionalinformation based on the skin of the individual and/or group ofindividuals.

In yet another embodiment, a data processing system analyzes data froman analyzer to estimate and/or determine an analyte property, such asconcentration using multiple types of data, such as from an externalsensor, from two or more radial positions, and/or with two or morefocusing depths.

In still another embodiment, an analyzer using light interrogates thesample using one or more of:

-   -   a spatially resolved system;        -   an incident light radial distance resolved system;        -   a controllable and variable incident light solid angle            system; and        -   a controllable and variable incident light angle system;    -   a time resolved system, where the times are greater than about        1, 10, 100, or 1000 microseconds;    -   a picosecond timeframe resolved system, where times are less        than about 1, 10, 100, or 1000 nanoseconds;    -   collection of spectra with varying radial distances between        incident light entering skin and detected light exiting the        skin;    -   an incident angle resolved system; and    -   a collection angle resolved system.

Data from the analyzer is analyzed using a data processing systemcapable of using the information inherent in the resolved system data.

In yet another embodiment, a data processing system usesinterrelationships of chemistry based a-priori spectral informationrelated to absorbance of a sample constituent and/or the effect of theenvironment, such as temperature, on the spectral information.

In yet still another embodiment, a data processing system uses a firstmapping phase to set instrument control parameters for a particularsubject, set of subjects, and/or class of subjects. Subsequently, thecontrol parameters are used in a second data collection phase to collectspectra of the particular subject or class of subjects.

In still yet another embodiment, a data processing system usesinformation related to contact pressure on a tissue sample site.

In another embodiment, a data processing system uses a combination ofany of:

-   -   spatially resolved information;    -   temporally resolved information on a time scale of longer than        about one microsecond;    -   temporally resolved information on a sub one hundred picosecond        timeframe;    -   incident photon angle information;    -   photon collection angle information;    -   interrelationships of spectral absorbance and/or intensity        information;    -   environmental information;    -   temperature information; and    -   information related to contact pressure on a tissue sample site.

In still yet another embodiment, a temporal resolution gatingnoninvasive analyzer is used to determine an analyte property of abiomedical sample, such as a glucose concentration of a subject usinglight in the near-infrared region from 1000 to 2500 nanometers.

In yet still another embodiment, an apparatus and method of use thereofis described using a plurality of time resolved sample illuminationzones coupled to at least one two-dimensional detector array monitoringa plurality of detection zones linked to the sample illumination zones.

Axes

Herein, axes systems are separately defined for an analyzer and for aninterface of the analyzer to a patient, where the patient isalternatively referred to as a subject and/or a person.

Herein, when referring to the analyzer, an x, y, z-axes analyzercoordinate system is defined relative to the analyzer. The x-axis is inthe direction of the mean optical path. The y-axis crosses the meanoptical path perpendicular to the x-axis. When the optical path ishorizontal, the x-axis and y-axis define a x/y horizontal plane. Thez-axis is normal to the x/y plane. When the optical path is movinghorizontally, the z-axis is aligned with gravity, which is normal to thex/y horizontal plane. Hence, the x, y, z-analyzer coordinate system isdefined separately for each optical path element. If necessary, wherethe mean optical path is not horizontal, the optical system is furtherdefined to remove ambiguity.

Herein, when referring to the patient, an x, y, z-axes patientcoordinate system is defined relative to a body part interfaced to theanalyzer. Hence, the x, y, z-axes body coordinate system moves withmovement of the body part. The x-axis is defined along the length of thebody part, the y-axis is defined across the body part. As anillustrative example, if the analyzer interfaces to the forearm of thepatient, then the x-axis runs longitudinally between the elbow and thewrist of the forearm and the y-axis runs across the forearm. Together,the x,y plane tangentially touches the skin surface at a central pointof the interface of the analyzer to the body part, which is referred toas the center of the sample site, sample region, or sample site. Thez-axis is defined as orthogonal to the x,y plane. Rotation of an objectis further used to define the orientation of the object to the samplesite. For example, in some cases a sample probe of the analyzer isrotatable relative to the sample site. Tilt refers to an off z-axisalignment, such as an off z-axis alignment of a probe of the analyzerrelative to the sample site.

Analyzer

Referring now and throughout to FIG. 1, an analyzer 100 is illustrated.The analyzer comprises at least: a light source system 110, a photontransport system 120, a detector system 130, and a data processingsystem 140, where the data processing system is optionally remotelylocated from the source/sample/detector system. In use the analyzer 100estimates and/or determines a physical property, a sample state, aconstituent property, and/or a concentration of an analyte.

Patient/Reference

Still referring to FIG. 1, an example of the analyzer 100 is presented.In this example, the analyzer 100 includes a sample interface 150, whichinterfaces to a reference material 160 and/or to a subject 170. Herein,for clarity of presentation a subject 170 in the examples isrepresentative of a person, animal, a prepared sample, and/or a patient.In practice, the analyzer 100 is used by a user to analyze the user,referred to as the subject 170, and/or is used by a medical professionalto analyze a patient.

Controller

Still referring to FIG. 1 and referring now to FIGS. 4 and 5, theanalyzer 100 optionally includes a system controller 180 or controller.The system controller 180 is used to control one or more of: the lightsource system 110 or a light source 112 thereof, the photon transportsystem 120, the detector system 130 or a detector 132 thereof, thesample interface 150, position of the reference 160 relative to thesample interface 150, position of the subject 170 relative to the sampleinterface 150, and/or communication to an outside system 190, such as apersonal communication device 192, a smart phone, and/or a remote system194 using a wireless communication system 196 and/or a hard wiredcommunication system 198. For example, the remote system includes a dataprocessing system, a data storage system, a data transfer system, and/ora data organization system.

Still referring to FIG. 1, the optional system controller 180 operatesin any of a predetermined manner or in communication with the dataprocessing system 140. In the case of operation in communication withthe data processing system 140, the controller generates controlstatements using data and/or information about the current state of theanalyzer 100, current state of a surrounding environment 162 outside ofthe analyzer 100, information generated by the data processing system140, and/or input from a sensor, such as a sample interface sensor 152or an auxiliary system 10 or an auxiliary sensor 12 thereof. Herein, theauxiliary system 10 is any system providing input to the analyzer 100.

Still referring to FIG. 1, the optional system controller 180 is used tocontrol: photon intensity of photons from the source using an intensitycontroller 122, wavelength distribution of photons from the source 110using a wavelength controller 124, physical routing of photons from thesource 110 using a position controller 126. and/or timing of photondelivery.

Still referring to FIG. 1, for clarity of presentation the optionaloutside system 190 is illustrated as using a personal communicationdevice 192, such as a smart phone. However, the personal communicationdevice 192 is optionally a cell phone, a tablet computer, a phablet, acomputer network, a personal computer, and/or a remote data processingcenter. Similarly, the smart phone also refers to a feature phone, amobile phone, a portable phone, and/or a cell phone. Generally, thepersonal communication device 192 includes hardware, software, and/orcommunication features carried by an individual that is optionally usedto offload requirements of the analyzer 100. For example, the personalcommunication device 192 includes a user interface system, a memorysystem, a communication system, and/or a global positioning system.Further, the personal communication device 192 is optionally used tolink to the remote system 194, such as a data processing system, amedical system, and/or an emergency system. In another example at leastone calculation of the analyzer 100 in noninvasively determining aglucose concentration of the subject 170 is performed using the personalcommunication device 192. In yet another example, the analyzer gathersinformation from at least one auxiliary sensor 12 and relays thatinformation and/or a processed form of that information to the personalcommunication device 192, where the auxiliary sensor is not integratedinto the analyzer 100. Optionally data from the analyzer 100 isprocessed in the cloud or a remote computing facility. Optionally, thepersonal communication device 192 is used as a portal between theanalyzer 100 and the cloud. Optionally, the remote system 194 is a dataprocessing center configured to receive signal from more than oneanalyzer and to return a calculated analyte concentration and/or ananalyte property to the corresponding analyzer and/or to a communicationdevice of the user of the corresponding analyzer.

Source

Herein, the source system 110 generates photons in any of the visible,infrared, near-infrared, mid-infrared, and/or far-infrared spectralregions. In one case, the source system generates photons in thenear-infrared region from 1100 to 2500 nm or any range therein, such aswithin the range of about 1200 to 1800 nm; at wavelength longer than anyof 800, 900, 1000, and 1100 nm; and/or at wavelengths shorter than anyof 2600, 2500, 2000, or 1900 nm.

Photon/Skin Interaction

Light interacts with skin through laws of physics to scatter andtransmit through skin voxels also referred to as volume pixels or skinvolumes.

Referring now to FIG. 2, for clarity of presentation and withoutlimitation, in several examples provided herein a simplifying andnon-limiting assumption is made, for some wavelengths, for sometemperatures, and for some optical configurations, that a mean photondepth of penetration, with subsequent detection at the incident surfaceof the subject, increases with mean radial distance between a photonillumination zone and a photon detection zone. For example, for photonstransmitting from a sample illumination zone, through the subject, andthrough a photon detection zone, such as at a subject/analyzerinterface:

-   -   at a first radial distance, photons penetrate with a mean        maximum depth of penetration into an epidermal layer of a        subject;    -   at a second larger radial distance, photons penetrate with a        mean maximum depth of penetration into a dermal layer of the        subject; and    -   at a third still larger radial distance, photons penetrate with        a mean maximum depth of penetration into a subcutaneous fat        layer of the subject.

Referring still to FIG. 2 and referring again to FIG. 5, a photontransport system 200 through skin layers of the subject 170 isillustrated. The photon transport system optionally uses one or moremirrors and/or lenses to direct light from a a source to a detector viaskin of a subject. In this example, the photon transport system 120guides light from a source 112 of the source system 110 to the subject170, optionally with an air gap 210 between a last optic of anillumination system and skin of the subject 170. Further, in thisexample, the photon transport system 120 irradiates skin of the subject170 over a narrow illumination zone, such as having an area of less thanabout 9, 4, 1, 0.25, 0.1, and/or 0.01 mm². Optionally, the photons aredelivered to the skin of the subject 170 through an optic or set ofoptics proximately contacting, but not actually contacting, the skin,such as within about 0.5, 1.0, or 2.0 millimeters of the skin.Optionally, the distance between the analyzer and the skin of thesubject 170 is maintained with a vibration and/or shake reductionsystem, such as is used in a vibration reduction camera or lens. Forinstance, shake of the sample site is monitored and the optical systemis dynamically adjusted to compensate for movement of the sample site.For clarity of presentation, the photons are depicted as entering theskin at a single point. A portion of the photons traverse, or moreparticularly traverse through, the skin to a detection zone. Thedetection zone is a region of the skin surface where the detector system130 gathers the traversing or diffusely reflected photons. Variousphotons traversing or diffusely scattering through the skin encounter astratum corneum, an epidermis 173 or epidermis layer, a dermis 174 ordermis layer, and subcutaneous fat 176 or a subcutaneous fat layer. Asdepicted in FIG. 2, the diffuse reflectance of the various photonsthrough the skin detected by the detection system 130 follow a varietyof optical paths through the tissue, such as shallow paths through theepidermis 173, deeper paths through the epidermis 173 and dermis 174,and still deeper paths through the epidermis 173, dermis 174, andsubcutaneous fat 176. However, for a large number of photons, thereexists a mean photon path for photons from a point entering the skinuntil exiting the skin and being detected by the detection system 130.In the illustrations, optical pathlengths are illustrated as straightlines and/or curved lines for clarity of presentation; in practice lighttravels in straight lines between multiple scattering events.

Pathlength

Herein, for clarity, without loss of generality and without limitation,Beer's Law is used to describe photon interaction with skin, thoughthose skilled in the art understand deviation from Beer's Law resultfrom sample scattering, index of refraction variation, inhomogeneity,turbidity, anisotropy, and/or absorbance out of a linear range of theanalyzer 100.

Beer's Law, equation 1, states that:

A a bC   (eq. 1)

where A is absorbance, b is pathlength, and C is concentration.Typically, spectral absorbance is used to determine concentration.However, the absorbance is additionally related to pathlength. Hence,determination of the optical pathlength traveled by the photons isuseful in reducing error in the determined concentration. Two methods,described infra, are optionally used to estimate pathlength: (1) spatialresolution of pathlength and (2) temporal resolution of pathlength.

Algorithm

The data and/or derived information from each of the spatial resolutionmethod and temporal resolution method are each usable with the dataprocessing system 140. Examples provided, infra, illustrate: (1) bothcases of the spatial resolution method and (2) the temporal resolutionmethod. However, for clarity of presentation and without limitation, thephotons in most examples are depicted as radially traversing from arange of input zones to a range of detection zones. Similarly, photonsare optionally delivered, simultaneously and/or as a function of time,from an input zone to a range of detection zones. Still further, photonsare optionally directed to a series of input zones, as a function oftime, and one or more detection zones are used to detect the photonsdirected to the series of input zones, simultaneously and/or as afunction of time. Yet still further, sets of photons of controlledwavelengths are delivered to corresponding incident positions on theskin and filters and/or detectors are configured at additional locationson the skin.

Spatial Resolution

The first method of spatial resolution contains two cases. Herein, in afirst case photons are depicted traversing from a range of input pointson the skin to a radially located detector to derive photon interrogatedsample path and/or depth information. However, in a second case, similarsystems optionally use a single input zone of the photons to the skinand a plurality of radially located detector zones to determineoptically sampled photon paths and/or depth information. Still further,a combination of the first two cases, such as multiple sources ormultiple illumination zones, and/or multiple detectors, is optionallyused to derive photon path information in the skin.

In a first system, still referring to FIG. 2 and referring now to FIG.3, the photon transit system 200 of FIG. 2 is illustrated where thephoton transport system 120 irradiates the skin of the subject 170 overa wide range of radial distances from the detection zone, such as atleast about 0.1, 0.2, 0.3, 0.4, or 0.5 millimeters from a center or edgeof the detection zone to less than about 1.0, 1.2, 1.4, 1.6, or 1.8millimeters from a center or edge of the detection zone. In thisexample, a mean photon path is provided as a function of radial distancefrom the illumination zone to the detection zone. Generally, over arange of about zero to less than about two millimeters from thedetection zone and in the range of 1100 to 2500 nm, the mean opticalpath of the detected diffusely scattered photons increases in depth as afunction of radial distance.

In the first case of the spatial resolution method, referring now toFIG. 4, the photon transit system 200 uses a vector or array ofillumination sources 400, of the source system 110, in a spatiallyresolved pathlength determination system. For example, the illuminationsources are an array of fiber optic cables, an array of light emittingdiodes, light passing through an array of optical filters, and/or anarray of illumination zones. In this example, a set of seven fiberoptics 401, 402, 403, 404, 405, 406, 407 are positioned, radially alongthe x,y plane of the subject 170 to provide a set of illumination zones,relative to a detection fiber at a detection zone. As illustrated thethird illumination fiber optic 403/detector 132 combination yields amean photon path having a third mean depth of penetration, d₃, for athird fiber optic-to-detector radial distance, r₃; the fifthillumination fiber optic 405/detector 132 combination yields a meanphoton path having a fifth mean depth of penetration, d₅, for a fifthfiber optic-to-detector radial distance, r₅; and the seventhillumination fiber optic 407/detector 132 combination yields a meanphoton path having a seventh mean depth of penetration, d₇, for aseventh fiber optic-to-detector radial distance, r₇. Generally, forphotons in the near-infrared region from 1100 to 2500 nanometers, both amean depth of penetration of the photons and a total optical pathlengthincreases with increasing illumination zone-to-detection zone distance,where the illumination zone-to-detection zone distance is less thanabout three millimeters.

In the second case of the spatial resolution method, referring now toFIG. 5, the photon transit system 200 uses a vector or array ofdetectors 500 in the detection system 130. For example, an illuminationzone source, such as a single fiber optic source, sends radiallydistributed light to an array of staring detectors or collection opticscoupled to a set of detectors. In this example, a set of seven detectors501, 502, 503, 504, 505, 506, 507 are positioned radially along the x,yplane to provide a set of detection zones relative to the illuminationzone. As illustrated the source 112/second detector 502 combinationyields a mean photon path having a second mean depth of penetration, d₂,for a second illumination zone-to-detection zone radial distance, r₂;the source 112/fourth detector 504 combination yields a mean photon pathhaving a fourth mean depth of penetration, d₄, for a fourth illuminationzone-to-detection zone radial distance, r₄; and the source 112/sixthdetector 506 combination yields a mean photon path having a sixth meandepth of penetration, d₆, for a sixth illumination-to-detection zoneradial distance, r₆. Again, generally for photons in the near-infraredregion from 1400 to 2500 nanometers both the mean depth of penetrationof the photons into skin and the total optical pathlength in skinincreases with increasing illumination zone-to-detection zone distance,where the illumination zone-to-detection zone distance, such as a fiberoptic-to-detector distance, is less than about three millimeters. Hence,data collected with an analyzer configured with a multiple detectordesign generally corresponds to the first case of a multiple sourcedesign, albeit with different sample volumes due to tissue layers,tissue inhomogeneity, and tissue scattering properties.

Referring again to FIGS. 4 and 5, the number of illumination zones,where light enters skin of the subject 170, from one or more sourceelements, is optionally 1, 2, 3, 4, 5, 10, 20, 50, 100 or more and thenumber of detection zones, where light exiting the skin of the subject170 is detected by one or more detection elements and/or systems, suchas 1, 2, 3, 4, 5, 10, 20, 50, 100, 500, 1000, 5000, 10,000, 50,000 ormore detection elements.

Two Dimensional Detector Array System

Referring now to FIG. 6A, a m×n two-dimensional detector array 134 isillustrated, which is an example of the detector 132 in the detectorsystem 130. Herein, the m×n two-dimensional detector array 134 isillustrated as a matrix of m columns by n rows, where m and n are each,not necessarily equal, positive integers, such as greater than 1, 2, 3,4, 5, 10, 20, 50, 100. Optionally, the two-dimensional detector array134 is of any geometric configuration, shape, or pattern. Preferably,but optionally, the two-dimensional detector array 134 is positionedperpendicular and axial to the optical light path at the detector.Optionally, the two-dimensional detector array 134 or a portion thereofis tilted off of the perpendicular axis, such as less than 1, 2, 3, 5,10, or 15 degrees toward the skin of the subject 170, which yields arange of applied pressures between the two-dimensional detector arrayand the skin when the two-dimensional detector array 134 or a layerthereon contacts the skin.

Referring now to FIG. 6B, an optional configuration of thetwo-dimensional detector array 134 is further described. Optionally, oneor more elements of the two-dimensional detector array 134 are coated orcoupled with an optical detector filter 620. In a first case, theoptical detector filter 620 is uniform across the two-dimensionaldetector array 134. In a second case, the optical detector filter 620comprises an array of filters, where individual elements, grids, orzones of the optical filter correspond to individual elements of thetwo-dimensional detector array 134. For example, a group of at least 1,2, 4, 9, 16, or 25 elements of the two-dimensional detector array 134are optically coupled with a first optical filter and a group of atleast 1, 2, 4, 9, 16, or 25 elements of the two-dimensional detectorarray 134 are optically coupled to a second filter. Optionally, anynumber of filter types are used with a single detector array, such as 1,2, 3, 4, 5, 10, 20 or more filter types. In a preferred embodiment, afirst, second, third, fourth, and fifth filter type correspond with peaktransmittance in ranges in the 1100 to 1450 nm range, 1450 to 1900 nmrange, 1100 to 1900 nm range, 1900 to 2500 nm range, or 1100 to 2500 nmrange, respectively, with lower transmittances, such as less than 50,25, or 10 percent at higher and/or lower frequencies. In a third case,the optical filter 134 comprises a repeating pattern of transmittancesand/or absorbances as a function of y, z-position.

Still referring to FIG. 6B, the two-dimensional detector array 134 isoptionally coupled to a detector optic/micro-optic layer 630. In a firstcase, individual optical elements of the micro-optic layer 630optionally:

-   -   alter a focal depth of incident light onto the two-dimensional        detector array 134;    -   alter an incident angle of incident light onto the        two-dimensional detector array 134;    -   focus on an individual element of the two-dimensional detector        array 134; and/or    -   focus on groups of detection elements of the two-dimensional        detector array 134.

In a second case, individual lines, circles, geometric shapes coveringmultiple detector elements, and/or regions of the micro-optic layeroptionally:

-   -   alter a focal depth of incident light onto a line, circle,        geometric shape, and/or region of the two-dimensional detector        array 134;    -   alter an incident angle of incident light onto a line, circle,        geometric shape, and/or region of the two-dimensional detector        array 134; and/or    -   focus onto a line, circle, geometric shape, and/or region of a        group of elements of two-dimensional detector array 134.

Further the individual optical elements of the micro-optic layer 630and/or the individual lines, circles, geometric shapes, or regions ofthe micro-optic layer 630 optionally are controlled by the systemcontroller 180 to change any of the focal depth and/or an incident angleof incident light as a function of time within a single data collectionperiod for a particular subject and/or between subjects.

Still referring to FIG. 6B, the optical detector filter 620 is:

-   -   optionally used with or without the detector optic/micro-optic        layer 630; and/or    -   optionally contacts, proximately contacts, or is separated by a        detector filter/detector gap distance from the two-dimensional        detector array 134.

Similarly, the detector optic/micro-optic layer 630 is:

-   -   optionally used with or without the optical detector filter 620;        and/or    -   optionally contacts, proximately contacts, or is separated by a        micro-optic/detector gap distance 632 from the two-dimensional        detector array 134.

Referring now to FIGS. 7(A-E), optionally and preferably an incidentoptic/two-dimensional detector array system 700 is enclosed in ahousing. For example, optionally and preferably, the detector array,first optical filter array, second optical filter array, and/or focusingoptic array are sandwiched together, where two or more of the stackedlayers are substantially contacting along an interfacing plane. Thefirst and/or second optical filter arrays are optionally placed alongthe optical axis on either side of the focusing optic/light gatheringarray. The housing serves a number of purposes, such as the ability toprevent dust/particulate infiltration; is an enclosure sealed againstmoisture, allowing the detectors to be operated below a dew point, suchas via use of 2, 3, or four layers of Peltier coolers; allows use of apartial vacuum within the enclosure;

and/or allows a substantially non-water containing gas to be placed inthe housing to minimize condensation.

Referring still to FIGS. 7(A-E), for clarity of presentation, theincident optic/two-dimensional detector array system 700 is illustratedin multiple representative configurations, without loss of generality orlimitation.

Referring now to FIG. 7A, a first example of the incidentoptic/two-dimensional array system 700 is illustrated with the photontransport system 120 used to deliver photons to the subject 170proximate the two-dimensional detector array 134. In a first example, aportion of photons from the photon transport system diffusely scatterthrough skin of the subject 170 and after radial movement emerge fromthe skin of the subject 170 where a portion of the incident photons aredetected by elements of the two-dimensional detector array 134. In afirst example, photons are illustrated travelling along: (1) a firstmean path, path₁, and are detected by a first detector element of thetwo-dimensional detector array 134 at a first, smaller, mean radialdistance from a tissue illumination zone of the photon transport systemand (2) a second mean path, path₂, are detected by a second detectorelement of the two-dimensional detector array 134 at a second, longer,mean radial distance from a tissue illumination zone of the photontransport system relative to path₁. In this first example, optionally:

-   -   a first element of the optical detector filter 620 is preferably        a filter designed for a shorter mean tissue pathlength, such as        about 0 to 1.5 millimeters, such as a combination band optical        filter with a peak transmittance in a range of 2000 to 2500 nm;    -   a second element of the optical detector filter is preferably a        filter designed for a longer mean tissue pathlength, such as        about 5.0 to 10 millimeters, such as a second overtone optical        filter with a peak transmittance in a range of 1100 to 1450 nm;        and    -   a third element of the optical detector filter is preferably a        filter designed for an intermediate mean tissue pathlength, such        as about 1.5 to 5.0 millimeters, such as a first overtone        optical filter with a peak transmittance in a range of 1450 to        1900 nm.

In the first example,

-   -   a first element of the detector optic/micro-optic layer 630 is        optionally configured to preferably collect incident skin        interface light having an angle aimed back toward the photon        transport system, which yields a slightly shorter mean tissue        pathlength, such as about 0.2 to 1.7 millimeters compared to an        optic that is flat/parallel relative to the skin of the subject        170;    -   a first element of the detector optic/micro-optic layer 630 is        optionally configured to redirect collected incident skin        interface light back away from the photon transport system 120        as illustrated, such as onto a center of a detector or detector        array element closer to the illumination zone;    -   a second element of the detector optic/micro-optic layer 630 is        optionally configured to preferably collect incident skin        interface light having an angle aimed away from the incident        illumination zone of the skin, which yields a slightly shorter        mean tissue pathlength compared to an optic that is        flat/parallel relative to the skin of the subject 170;    -   a second element of the detector optic/micro-optic layer 630 is        optionally configured to redirect collected incident skin        interface light back toward the incident skin illumination zone,        such as onto a center of a detector or detector array element        further from the illumination zone;    -   a third element of the detector optic/micro-optic layer 630 is        optionally flat/parallel relative to a mean plane between the        skin of the subject 170 and the two-dimensional detector array        134.

As described, supra, the individual optical elements of the micro-opticlayer 630 and/or the individual lines, circles, geometric shapes, orregions of the micro-optic layer 630 are optionally dynamicallycontrolled by the system controller 180 to change any of a detectorlayer incidence acceptance angle, the focal depth, an incident angle,and/or an emittance angle or exit angle as a function of time within asingle data collection period for a particular subject and/or betweensubjects.

Still referring to FIG. 7A, an optional micro-optic layer/detector arraygap 632 is illustrated between the detector optic/micro-optic layer 630and elements of the two-dimensional detector array 134, such as a gapless than 0.2, 0.5, 1, 2, 5, or 10 millimeters. Further, an optionalspacer gap 121 is illustrated between a final incident optic of thephoton transport system 120 and any of the two-dimensional detectorarray 134, the optical detector filter 620, and/or the detectoroptic/micro-optic layer 630, such as a gap of less than about 0.1, 0.2,0.3, 0.4, 0.5, 0.75, and/or 1.0 millimeter.

Referring now to FIG. 7B, a second non-limiting example of the incidentoptic/two-dimensional detector array system 700 is illustrated with thephoton transport system 120 used to deliver photons to the subject 170proximate a first side of the two-dimensional detector array 134, wherethe array has n detector elements, where n is a positive integer greaterthan three. In this second example, ten radial distances to ten detectorelements are illustrated. In this example, some radial distances areequal, such as a first radial distance to detector elements 1 and 5 anda second radial distance to detector elements 2 and 4. Generally,detector elements are optionally grouped or clustered into radialdistances relative to an illumination zone of 1, 2, 3, or more incidentlight directing elements where each group or cluster is individuallyassociated with an average mean optical probed tissue pathlength,subsequently used in pathlength resolution, and/or analyte concentrationestimation.

Still referring to FIG. 7B, optionally, different clusters of radialdistances are treated optically differently, such as with a differentoptical detector filter 620. Representative and non-limiting examplesinclude:

-   -   a combination band filter for filtering photons having mean        radial distances of 0 to 1 millimeter, the combination band        filter comprising:        -   a transmittance greater than seventy percent at 2150 nm,            2243, and/or 2350 nm, and/or        -   an average transmittance of greater than seventy percent            from 2100 to 2400 nm and an average transmittance of less            than twenty percent from 1100 to 1900 nm and/or from 2400 to            2600 nm;    -   a first overtone band filter for filtering photons having mean        radial distances of 0.3 to 1.5 millimeters, the first overtone        filter comprising:        -   a transmittance greater than seventy percent at 1550 nm,            1600, and/or 1700 nm, and/or        -   an average transmittance of greater than seventy percent            from 1500 to 1800 nm and an average transmittance of less            than twenty percent from 1100 to 1400 nm and/or from 2000 to            2600 nm;    -   a combination band/first overtone band filter for filtering        photons having mean radial distances of 0 to 1.5 millimeters,        the combination/first overtone filter comprising:        -   a transmittance greater than seventy percent at 1600 and            2100 nm, and/or        -   an average transmittance of greater than seventy percent            from 1500 to 2300 nm and an average transmittance of less            than twenty percent from 700 to 1400 nm and/or from 2500 to            2800 nm;    -   a second overtone band filter for filtering photons having mean        radial distances of 0.5 to 3.0 millimeters, the second overtone        filter comprising:        -   a transmittance greater than seventy percent at 1200 nm,            1300, and/or 1400 nm, and/or        -   an average transmittance of greater than seventy percent            from 1100 to 1400 nm and an average transmittance of less            than twenty percent from 700 to 1000 nm and/or from 1500 to            2000 nm;    -   a first overtone band/second overtone band filter for filtering        photons having mean radial distances of 0.5 to 3.0 millimeters,        the first overtone band/second overtone band filter comprising:        -   a transmittance greater than seventy percent at 1300 and            1600 nm, and/or        -   an average transmittance of greater than seventy percent            from 1200 to 1700 nm and an average transmittance of less            than twenty percent from 700 to 1000 nm and/or from 2000 to            3000 nm;    -   a sloping overtone band filter or step function overtone band        filter for filtering photons having mean radial distances of 0.5        to 3.0 millimeters, the sloping overtone band filter comprising:        -   a mean transmittance greater than ten percent at 1300 nm,            less than fifty percent at 1300 nm, and greater than seventy            percent at 1600 nm, and/or        -   an average transmittance between 1100 and 1300 nm in the            range of ten to fifty percent and an average transmittance            between 1500 and 1700 nm of greater than seventy percent            with optional out of band blocking from 700 to 1000 nm            and/or from 2500 to 3000 nm of greater than ninety percent;            and/or    -   a luminance filter for filtering photons having mean radial        distances of 0 to 5 millimeters, the luminance filter        comprising:        -   an optical spacing element designed to maintain focal            length;        -   a mean transmittance greater than seventy percent from 1100            to 1800 nm, and/or        -   a mean transmittance greater than seventy percent from 1100            to 2400 nm and an average transmittance of less than twenty            percent from 700 to 1100 nm and/or from 2000 to 2600 nm.

Referring now to FIGS. 7B, 7C, and 7D, the photon transport system 120is illustrated as delivering light to an edge, corner, and interiorregion of the two-dimensional detector array 134, respectively.Descriptions, herein, to the edge, corner, or interior illuminationoptions optionally apply to the other cases.

Referring again to FIG. 7B, the photon transport system 120 isillustrated delivering photons using at least one fiber optic and/orthrough one or more optics to a point or illumination zone along an edgeof the two-dimensional detector array 134. For clarity of presentation,in a first case, the photon transport system 120 is illustrateddelivering photons to a center of an edge of the two-dimensionaldetector array 134; however, the photon transport system 120 optionallydelivers photons to any point along the edge of the two-dimensionaldetector array 134 and/or at any distance from an edge or corner of thetwo-dimensional detector array.

Still referring to FIG. 7B, as illustrated the photon transport systemdelivers photons that are detected with an array of mean pathlengths andassociated mean depths of penetration into the tissue of the subject170, at each detector element. For example, the first detector element,1, detects photons having a first mean pathlength for a firstillumination point, herein denoted b_((pathlength, illuminator)). In thefirst case, using a simplifying assumption of tissue homogeneity forclarity of presentation, the mean probed pathlength is the same at thefirst and fifth detector elements. Similarly, the mean probed pathlengthis similar and/or tightly grouped at the second and fourth detectorelement. In addition, groups of detector elements observe photonstraversing similar or grouped pathlengths. For example, a firstsub-group of the first, sixth, and seventh detector elements observesimilar probed tissue pathlengths and depths of penetration. Similarly,a second sub-group of the fifth, ninth, and tenth detector elementsobserve similar probed tissue pathlengths and depths of penetration. Inthis case, the first sub-group and second sub-group are optionallyplaced into a single group as the first sub-group and second sub-groupobserve similar, exact if the tissue is homogenous, probed tissuepathlengths. Similarly, a first sub-group is optionally one, two, three,or more elements of a first column of detector elements and a secondsub-group is optionally one, two, three, or more elements of a secondcolumn of the detector elements. Generally, the detector elements areoptionally treated individually or in sub-groups, such as by distancefrom a mean sample illumination point, sub-groups of one or more rows ofdetector element, sub-groups of one or more columns of detectorelements, and/or groups of sub-groups.

Still referring to FIG. 7B, any two-dimensional detector array 134element, sub-group, column, row, region, and/or group is optionallyindividually coated or coupled to any filter, such as the filtersdescribed supra, and/or is optionally individually coupled with afocusing optic and/or a dynamic focusing optic, as further described,infra.

Referring now to FIG. 7C, a second case of an illumination optic and/ora group of illumination optics of the photon transport system 120 usedto illuminate an illumination zone relative to a corner of thetwo-dimensional detector array 134 is illustrated. As with the firstside illumination case, individual elements, sub-groups, and/or groupsof detector elements observe at differing radial distances from theillumination zone where the differing radial distances havecorresponding average observed tissue pathlengths, depths ofpenetration, and/or sampled regions of skin of the subject 170. Here,three groups or detection zones are illustrated. The first group 710 isillustrated as detection elements 1, 2, 3, 4, 5, and 6, where thecommonality is a short radial distance between the illumination zone andthe detection zone, such as used for the combination band spectralregion and/or for small mean depths of penetration of the photons intothe tissue of the subject 170. The second group 720 is illustrated withlong rising dashes, where the commonality is a medium radial distancebetween the illumination zone and the detection zone, such as used forthe first overtone spectral region. The third group 730 is illustratedwith short falling dashes, where the commonality is a long radialdistance between the illumination zone and the detection zone, such asused for the second overtone spectral region. As described, supra, anydetector element, sub-group, and/or group is optionally associated withan individual filter, an individual optic, an individual dynamic optic,and/or a group of optics. Further, any detector element, sub-group,and/or group is optionally associated with any position and/orwavelength of illuminators, such as with a light-illuminating diodeillumination array.

Referring now to FIG. 7D, a third case of an illumination optic and/or agroup of illumination optics of the photon transport system 120 used toilluminate an illumination zone within a section within thetwo-dimensional detector array 134 is illustrated. As with the firstside illumination case and the second corner illumination case,individual elements, sub-groups, and/or groups of detector elementsobserve at differing radial distances from the illumination zone wherethe differing radial distances have corresponding average observedtissue pathlengths, depths of penetration, and/or sampled regions ofskin of the subject 170. Here, two groups or detection zones areillustrated. The third group 740 is a first section, arc, quadrant,zone, ring, square, rectangle, and/or polygon of detection elements at afirst range of distances from the illumination zone, illustrated herewith detector elements intersecting with a long-dashed/square shape. Thefourth group 750 is a second section, arc, quadrant, zone, ring, square,rectangle, and/or polygon of detection elements at a second range ofdistances from the illumination zone, shown here with detector elementsintersecting with a short-dashed/square shape. The fourth group 740 andfifth group 750 are illustrative of n groups where n is a positiveinteger of 2, 3, 4, 5, 10 or more where individual groups differ by 1,2, 3, 4 or more cross-sectional distances of a detector element. Asdescribed, supra, any detector element, group, sub-group, and/or groupis optionally associated with an individual filter, an individual optic,and/or an individual dynamic optic.

Still referring to FIG. 7D, in one optional filter arrangement, opticalfilters are stacked. For example, a first optical filter is a first longpass or a first short pass filter covering a wide range of firstdetector elements; a second optical filter is stacked relative to thefirst optical filter along the x-axis, which is the optical axis. Thesecond optical filter is a second long pass, a second short pass, or aband pass filter covering a subset of the first detector elements. Forexample, the first optical filter is a long pass filter passingwavelengths longer than 1100 nm covering all of the fourth group 740 andfifth group 750, and the second optical filter is a long pass filterpassing wavelength longer than 1450 nm covering all of the fifth group,which yields a first overtone filter for the fourth group 740 and afirst and second overtone filter for the fifth group 750. Combinationsof stacked filters for various groups include any of 2, 3, 4, or morefilters described herein, such as the combination band filter, the firstovertone band filter, the combination band/first overtone band filter,the second overtone band filter, the first overtone band/second overtoneband filter, the sloping overtone bands filter, and the luminance filterdescribed, supra, in the description of FIG. 7B. The inventor notes thatcutting larger stackable filters reduces costs and more importantlylight loss associated with placing individual filters over individualdetector elements of the two-dimensional detector array 134.

Referring now to FIG. 7E, a fourth example of multiple illuminationzones from the photon transport system 120 positioned about and within,not illustrated, the two-dimensional detector array 134 is illustrated.In this fourth example, a matrix of illuminators, herein represented bya single column for clarity of presentation, are denoted as illuminatorsa-z. At a given point in time, any set or subset of the matrix ofilluminators are used to deliver photons to the tissue of the subject170. For example, at a first point in time, illuminators a-b are used;at a second point in time illuminators a-d are used; at a third pointtime illuminators d-g are used, and so on. As illustrated, illuminatorsa-d are used and a detection element m,n is used. Generally, sets ofilluminators are optionally used as a function of time where theilluminators define the number of photons delivered and provide a firstpart of a illumination zone-to-detection zone distance and selecteddetector elements as the same function of time define the second part ofthe illumination zone-to-detection zone distance. Optionally, theillumination array a light-emitting diode (LED) array used incombination with a filter array allowing an analyzer without use of atime-domain interferometer and/or a grating.

Referring again to FIGS. 7B-E, notably, detector elements associatedwith a first sub-group or first group at a first point in time areoptionally associated with an n^(th) sub-group or n^(th) group at an^(th) point in time when the same and/or a different set ofilluminators are used, where n is a positive integer of 2, 3, 4, 5, 10or more.

Multiple Two-Dimensional Detector Arrays

Referring now to FIGS. 8A-D, a multiple luminance/multiple detectorarray system 800 is described. Generally, one and preferably two or moreillumination zones are provided by the photon transport system withinand/or about two or more detector arrays, such as two or more of thetwo-dimensional detector arrays 134. For clarity of presentation andwithout loss of generality, several examples are provided, infra, of themultiple luminance/multiple detector array system 800.

Referring now to FIG. 8A, a first example of the photon transport system120 delivering light to the skin of the subject 170 at multipleillumination positions relative to two or more detector arrays, such asa first detector array 702 and a second detector array 704, is provided.In this first example, the photon transport system delivers light: (1)by the side 802, (2) removed from the side 804, (3) at the corner 806,and/or (4) around the corner 808 of a detector array, such as the seconddetector array 704. As illustrated, illumination zones are provided in afirst column and in a second column relative to the side of the seconddetector. The first column 802 and the second column 804 of illuminatorsare illustrated proximately touching, with a first illuminator/detectorgap 812, an edge of the second detector array 704 and with a secondilluminator/detector gap 814 from the first detector array 702, wherethe first illuminator/detector gap 812 and the secondilluminator/detector gap 814 are optionally different by greater thanten percent and are, respectively, less than and greater than, about 1,½, ¼, ⅛, 1/16, or 1/32 of a millimeter.

Referring again to FIGS. 7(A-E) and 8A, any detector array is optionallytilted along the y- and/or z-axes to yield varying degrees of forceapplied to a sampled tissue sample as a function of detector positionwhen directly contacting the tissue or indirectly contacting the tissuevia a fronting detector layer during sampling. The varying pressureresults in data comprising varying and/or controllable pressure for easein subsequent data processing, such as via binning, grouping,correlations, and/or differential measures.

Still referring to FIGS. 7(A-E) and 8A, any detector array is optionallydifferentially cooled along the y- and/or z-axes, such as with a Peltiercooler on one side of the detector array, to yield varying degrees oftemperature as a function of detector position when directly contactingthe tissue or indirectly contacting the tissue via a fronting detectorlayer during sampling. The varying temperature results in datacomprising varying and/or controllable temperature for ease insubsequent data processing, such as via binning, grouping, correlations,and/or differential measures, such as for analysis of temperaturesensitive absorbance bands and/or water absorbance bands.

Multiple Pathlengths

Referring now to FIG. 8B, a second example of the photon transportsystem 120 delivering light to the skin of the subject 170 at multipleillumination positions relative to two or more detector arrays isprovided.

Illuminator Arrays

In this example, an illuminator array 810 is illustrated. Generally, theilluminator array 810 is a set of illumination points and/or anillumination area of any geometric cross-sectional shape along the y-,z-axes. Referring still to FIG. 8B, three examples of illuminator arrays810 are illustrated: a first illuminator array 812 comprising an aboutcircular illumination pattern, here represented as nineteen illuminationareas and/or a rough circle of illumination; a second illuminator array814, here represented as twelve illumination regions and/or a subset ofthe first illuminator array 812; and a third illuminator array 816,which represents an about square and/or rectangular illumination array,which does not overlap any of the first illuminator array 812.Additionally, a fourth illuminator array optionally overlaps a portionof any other illuminator array as a function of time, not illustrated.

Detector Arrays

Still referring to FIG. 8B, an illustrative example of a threeilluminator area system coupled to a four area detection system isdescribed, where the four area detection system comprises: a firstdetector array 702, a second detector array 704, a third detector array706, and a fourth detector array 708. In this second example, fourdetector arrays are illustrated about the three illumination arrays 812,814, 816, which are representative of any number of illuminationelements and/or any number of illumination arrays. For ease ofpresentation, this section refers to a center mean illumination pointfor each of the three illumination arrays 812, 814, 816, which in thepresent case is the center of the symmetrically illustrated lightillumination arrays labeled X, Y, and Z, respectively.

Still referring to FIG. 8B and now referring to the first detector array702 and the first illumination array 812 having center X, the inventornotes that the first row of the detector array contains detectorelements at three optical pathlengths from the center of theillumination array. A first pathlength, b₁, is observed at the centerelement of the first row of detector elements. A second pathlength, b₂,is observed with each of the detector elements, in the first row of thedetector array, adjacent the center detector element in the first row ofthe first detector array 702. Data collected at the redundantpathlengths comprise multiple uses, such as precision determination,outlier detection, tissue variation estimation, and/or tissue mapping,as described infra. A third pathlength, b₃, is observed with each of thedetector elements at the outer ends of the first row of the firstdetector array 702. Similarly, the second row of the detector arrayobserves three additional pathlengths, described here as the fourth,fifth, and sixth pathlengths, b₄, b₅, N. Similarly, the third, fourth,and fifth rows of the detector array contains fifteen additionaldetector elements observing an additional three pathlengths per row ornine additional pathlengths, b₇-b₁₅. The inventor notes that the firstdetector array 702, represented as a 5×5 matrix of detector elements, isoptionally an m×n array of detector elements, as described in relationto FIG. 6A, with a corresponding number of observed mean opticalpathlengths and mean optical depths.

Still referring to FIG. 8B, as described, supra, in relation to FIG. 5and further described, infra, as the median pathlength of the probingphotons increases, the depth of penetration of the mean photon increasesfor each wavelength in the range of 1100 to 2500 nm until an absorbancelimit of detection is reached. Thus, as illustrated, the first detectorarray 702 is configured to observe fifteen pathlengths, three per row,where ten of the pathlengths are observed twice with intentionallyseparated sample tissue volumes.

Still referring to FIG. 8B and referring now to the second detectorarray 704 and still referring to the first illuminator array 812, thesecond detector array 704 is rotated about the x-axis relative to thefirst detector array 702 placing a corner of the second detector arraycloset to the mean illumination point of the first illumination array,X, as opposed to the first detector array 702 having a side closest tothe mean illumination point, X. Rotation of the second detector array704 allows another set of observed pathlengths, even when a duplicatedetector array design is used. For example, as illustrated the corner ofthe second detector array 704 represents a sixteenth pathlength, b₁₆.Similarly, the second diagonal of the second detector array 704 containstwo additional detector elements observing a seventeenth pathlength,b₁₇, in duplicate due to symmetry about a line through the center of thefirst illuminator array 812 and nearest corner of the second detectorarray 704. Similarly, the third to ninth diagonal of the second detectorarray 704 contain twenty-two additional detector elements observingthirteen additional pathlengths, b₁₈-b₃₀.

Still referring to FIG. 8B and referring now to the third detector array706 and still referring to the first illuminator array 812, the thirddetector array 706 is positioned opposite the second detector array 704.The symmetrical positioning of the third detector array 704 relative tothe second detector array 704 and the first illuminator array 812 yieldspathlengths mirroring those observed using the second detector array;particularly, pathlengths sixteen to thirty, b₁₆-b₃₀. The mirroredpathlengths allows repetitive data for an internal check of results,validation of results, outlier detection, concentration estimationbounding, and/or additional algorithmic uses. Notably, by merelyshifting a detector array and/or a source array along the y-z-axes,instead of repeated pathlengths, the new illuminator/detectorcombination will observe new pathlengths; twenty-five new pathlengthsfor the illustrated 5×5 detector element array.

Still referring to FIG. 8B and referring now to the fourth detectorarray 708 and still referring to the first illuminator array 812, thefourth detector array 708 is rotated an angle theta relative to thefirst detector array 702. The rotation of the fourth detector array 708breaks symmetry along a line from the center of the first illuminatorarray 812, X, and a center of the fourth detector array 708. Now,intentionally, lacking rotational symmetry the fourth 5×5 detector arrayobserves twenty-five additional pathlengths, b₃₁-b₅₅, compared with thefifteen pathlengths observed by the first detector array 702 and fifteendistinct pathlengths observed using the second detector array 704.

Still referring to FIG. 8B and now referring to the second illuminatorarray 814, the center of the second illuminator array 814, Y, is offsetalong the y-z-axes relative to the center of the first illuminatorarray, X, which breaks symmetry relative to each of the four detectorarrays 702, 704, 706, 708. The intentional breaking of the symmetryallows the four detector arrays 702, 704, 706, 708 to observe onehundred (25×4) new pathlengths by merely changing an opticalillumination configuration. Similarly, now referring to the thirdilluminator array 816, moving the center of illumination to a thirdpoint, Z, yields an additional one hundred new observed pathlengths(25×4). To illustrate the number of observed pathlengths still further,use of four 50×50 detector arrays without symmetry relative to fiveillumination patterns yields 50,000 (2500 detectors/array×4 arrays×5illumination zones) observed pathlengths. Detector arrays of m×ndimension where m and/or n are independently any positive integer of 1,2, 3, 5, 10, 100, 500, 100 or more thus yields tens, hundreds,thousands, and/or millions of detector elements. Hence, with atwo-dimensional detector array, even using one detector design, and anillumination source, even statically positioned, may readily yieldhundreds of thousands or millions of observed pathlengths in a period ofless than 1, 2, 3, 4, 5, 10, 20, or 30 seconds as the detectors areoptionally used in parallel.

Filters

Herein, optical filters optically coupled with elements of the detectorarrays are described.

Longpass Filters

Referring now to FIG. 9A, a series of longpass filters are described. Alongpass filter is an optical interference and/or coloured glass filterthat attenuates and/or blocks shorter wavelengths and transmits and/orpasses longer wavelengths over a range of wavelengths. Longpass filtersoptionally have a high slope described by a cut-on wavelength at awavelength passing fifty percent of peak transmission. Herein, longpassfilters refer to filters comprising a fifty percent cut-on wavelength inthe range of 900 to 2300 nm. More preferably, for analysis of tissuespectra, the inventor has determined that longpass filters complementingwater absorbance bands offer multiple advantages relating to detectordynamic range.

Referring still to FIG. 9A and referring now to FIG. 9B, a firstlongpass filter 912 is illustrated comprising a fifty percent cut-onwavelength in the range of 1850 to 2050 nm, such as at about 1900, 1950,or 2000 nm. The first longpass filter 912 is designed to transmitphotons in a region referred to herein as a ‘combination band region’950, which comprises a first region of low water absorbance and threeglucose absorbance bands. The inventor has determined that by having thesharp, often temperature sensitive and/or difficult to analyze regiondue to rapid changes in transmittance as a function of wavelength,cut-on wavelength in the wavelength range of the large water absorbanceband spectral feature, that the filter weaknesses are masked by thewater absorbance band while the filter strengths are optimize, asdescribed herein. First, the first longpass filter 912 transmits a highpercentage of light, such as greater than 70, 80, or 90 percent, in thedesirable range of 2100 to 2350 nm where water absorbance 1310 andscattering combine to yield detected photons in the glucose rich dermislayer of skin and where glucose has three prominent absorbance bands at2150, 2272, and 2350 nm. Second, the first longpass filter 912 has atransition cut-on range, that hinders analysis due to the rapid changein transmittance as a function of wavelength and is susceptible totemperature induced spectral shifts, that is placed in a region wherewater absorbance prevents detection of photons penetrating into thedermis, thereby eliminating the problem. Third, the first longpassfilter 912 has a blocking range from a detector cut-on of about 700 nmto about 1900 nm, which blocks photons otherwise filling a dynamic rangeof an element of the detector array, which allows an enhancedsignal-to-noise ratio, using proper detector gain electronics and/orintegration time, in the desirable range of 2100 to 2350 nm. Theinventor notes that the water absorbance band at circa 2500 nm functionsas a natural shortpass filter, which combines with the first longpassfilter 912 to form a combination band bandpass filter.

Referring still to FIG. 9A and FIG. 9B, a second longpass filter 914 isillustrated comprising a fifty percent cut-on wavelength in the range of1350 to 1490 nm, such as at about 1375, 1400, 1425, 1450, or 1475 nm.The second longpass filter 914 is designed to transmit photons in aregion referred to herein as a ‘first overtone region’ 960, whichcomprises a second region of low water absorbance and three glucoseabsorbance bands. As with the first longpass filter 912, the secondlongpass filter 914 is designed to function in a complementary mannerwith water absorbance of tissue. Particularly, the second longpassfilter 914 transmits three prominent glucose bands in the first overtoneregion centered at circa 1640, 1692, and 1730 nm, which are in a regionwhere the dominant absorber water and tissue scattering combine to yielddetectable photons having sampled the glucose rich dermal layer oftissue in diffuse reflectance mode. Further, the second longpass filterblocks/substantially blocks light from about 700, 800, 900, 1000, and/or1100 to 1450 nm, which would otherwise contribute to filling a dynamicrange of a detector array element. Blocking the second overtone light,described infra, thus allows full use of a dynamic range of a detectorin the first overtone region and a correlated enhancement in asignal-to-noise ratio of the three first overtone glucose absorbancebands. Still further, the second longpass filter 914 benefits from thewater absorbance band at 1950 nm, which functions as a natural shortpassfilter to the second longpass filter 914 forming a first overtonebandpass filter from about 1450 to 2000 nm or a spectral region therein.

The inventor notes that traditional spectroscopic analysis of tissueusing near-infrared light does not: (1) combine light from thecombination band region 950 with light from the first overtone region960 using separate detectors, which are optionally individuallyoptimized for a spectral region, or (2) use separate longpass filters,bandpass filters, or optics coupled to the multiple detectors tosimultaneously enhance spectral quality of the first overtone region andcombination band region.

The inventor has determined that the three glucose absorbance bands inthe combination band region are linked at an atomic/chemical energylevel to the three glucose absorbance bands in the first overtoneregion. Hence, detection of signals from corresponding bands of thecombination band region and first overtone region are optionallycompared to enhance glucose concentration estimations.

Referring still to FIG. 9A and FIG. 9B, a third longpass filter 916 isillustrated comprising a fifty percent cut-on wavelength in the range of700 to 1200 nm, such as at about 800, 900, 1000, or 1100 nm. The thirdlongpass filter 916 is designed to transmit photons in a region referredto herein as a ‘second overtone region’ 970 from about 1000 or 1100 to1400 nm. Similar to the first and second longpass filters 912, 914, thethird longpass filter 916 is designed to optimize signal-to-noise ratiosin the second overtone region, function with the use of water absorbancebands at 1450 and 1900 nm as natural shortpass filters, and to be usedwith detector array elements observing photons having sampled at leastthe dermis skin layer. It is noted that the first, second, and thirdlongpass filters 912, 914, 916 are illustrated with differing maximumlight throughput for clarity of presentation, but each optionallyfunction as a longpass filter as described supra.

Shortpass Filters

Referring now to FIG. 10, a series of shortpass filters are illustrated.A shortpass filter is an optical interference and/or coloured glassfilter that attenuates and/or blocks longer wavelengths of light andtransmits and/or passes shorter wavelengths of light over a spectralrange. Herein, shortpass filters refer to filters comprising a fiftypercent cut-off wavelength in the range of 1400 to 3000 nm. Morepreferably, for analysis of tissue spectra, the inventor has determinedthat shortpass filters complementing water absorbance bands offermultiple advantages relating to detector dynamic range. A shortpassfilter preferable passes greater than 60, 70, 80, or 90 percent of lightin the passed spectral region and transmits less than 1, 5, 10, 20, 30,or 40 percent of the light in the attenuated spectral region.

Referring again to FIG. 10 and referring now to FIG. 11A, a firstshortpass filter 1012 is illustrated comprising a fifty percent cut-offwavelength in the range of 2350 to 3000 or more nanometers. The firstshortpass filter 1012 is designed to transmit photons in the secondovertone 970, first overtone 960, and/or combination band region 950.The first shortpass filter 1012 is designed to block infrared heat atwavelengths greater than about 2350 nm, where otherwise transmitted heatwould alter temperature of parts of the tissue and result in shifting ofoxygen-hydrogen water band positions. Preferably, the first shortpassfilter 1012 is combined with a longpass filter, such as with the firstlongpass filter 912 to form a combination band bandpass filter 1130 forthe combination band region, with the second longpass filter 914 to forma bandpass filter for the first overtone/combination band spectralregion, or with the third longpass filter 916 to form a secondovertone/first overtone/combination band bandpass filter.

Referring again to FIG. 10 and FIG. 11A, a second shortpass filter 1014is illustrated comprising a fifty percent cut-off wavelength in therange of 1800 to 2100 nm, such as at about 1900, 1950, or 2000nanometers. The second shortpass filter 1014 is designed to transmitphotons in the second overtone 970 and first overtone 960 regions. Thesecond shortpass filter 1014 is designed to block infrared heat atwavelengths greater than about 2000 nm, where otherwise transmitted heatwould alter temperature of parts of the tissue and result in shifting ofoxygen-hydrogen water band absorbance positions of molecules in theskin. Preferably, the second shortpass filter 1014 is combined with alongpass filter, such as with the second longpass filter 914 to form afirst overtone bandpass filter 1120 for the first overtone region orwith the third longpass filter 916 to form a second overtone/firstovertone bandpass filter.

Referring again to FIG. 10 and FIG. 11A, a third shortpass filter 1016is illustrated comprising a fifty percent cut-off wavelength in therange of 1300 to 1600 nm, such as at about 1400, 1450, or 1500nanometers. The third shortpass filter 1016 is designed to transmitphotons in the second overtone 970 and optionally part of the firstovertone 960 spectral regions. The third shortpass filter 1130 isdesigned to block photons from about 1600 to 2500 nm than wouldotherwise contribute to filling a detector well depth and/or dynamicrange of a near-infrared detector, such as an indium/gallium/arsenidedetector. Preferably, the third shortpass filter 1016 is combined with alongpass filter, such as with the third longpass filter 916, to form asecond overtone bandpass filter 1110 for the second overtone regionand/or a portion of the first overtone region, such as about 1500 to1580 nm.

As illustrated in FIG. 11A, the fifty percent cut-off of the shortpassfilter is preferably in a region of strong water absorbance to maximizetransmitted photons while minimizing detection of out of band photons byusing the water absorbance properties of skin.

Referring now to FIG. 11B, narrowband bandpass filters or bandpassfilters are optionally used to enhance the signal-to-noise ratio in anarrow spectral region, such as about 25, 50, 100, 150, or 200 nm wide.Optionally, the bandpass filters are associated with a light intensitylimiting sample constituent, such as water. For example, in thecombination band spectral region 950, a minimum water absorbance isobserved at about 2270 with higher water absorbances observed at bothlonger and shorter wavelengths, such as at about 2150 or 2350 nm.Without an optical filter or an independent wavelength selection device,a multiplexed signal, such as obtained using a Fourier transformnear-infrared spectrometer, will dominantly fill a well of a detectorwith photons from the spectral region transmitting more light, such asat about the water absorbance minimum, while obtaining fewer photonsfrom spectral regions of higher absorbance. Thus, the signal-to-noiseratio in regions of higher water absorbance is degraded compared to useof the narrowband bandpass filter in a region of higher water absorbanceand/or total observed absorbance. A narrowband bandpass filter or a setof narrowband bandpass filters in combination with multiple detectors,such as a two-dimensional detector array allows for each region to fullyuse a dynamic range of the detector elements, if properly matched withamplifier circuitry and integration time. For example, a firstnarrowband bandpass filter 1150 is optionally used at a first set ofwavelengths correlated with a larger water absorbance. Similarly, asecond narrowband bandpass filter 1160 and/or a third narrowbandbandpass filter 1170 are optionally used at spectral regions ofintermediate and low water absorbance, respectively. Generally, nnarrowband bandpass filters are optionally used, where n is a positiveinteger of 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 50 or more. Combined,signals collected, preferably simultaneously, with the set of narrowbandbandpass filters allows coverage of large regions of the near-infraredregion where signal-to-noise ratios are significantly enhanced for givensubsets of the near-infrared spectral region associated with eachnarrowband bandpass filter.

The narrowband filters are optionally used in combination with an arrayof LEDs, where LED wavelength regions are optionally radially configuredrelative to the associated filter in the filter arrays as a function ofwater absorbance. For instance, a first LED illuminating at a wavelengthwhere water absorbance in skin is high is positioned close to one ormore filters passing light emitted by the first LED, such as withinabout 0.2 to 0.75 millimeters. Similarly, a second LED illuminating at awavelength where water in skin has medium absorbance is positioned at anintermediate distance from the one or more filters passing light emittedby the second LED, such as within about 0.5 and 1.5 millimeters.Similarly, a third LED illuminating at a wavelength where water in skinhas low absorbance is positioned at a still further distance from theone or more filters passing light emitted by the third LED, such aswithin about 1.0 and 2.5 millimeters. Generally, the distance between anLED and a filter configuration passing light of the LED is a function ofabsorbance and/or scattering, such as according to equation 2,

$\begin{matrix}{{\left. {distance} \right.\sim\frac{1}{abs}}*\frac{1}{scattering}} & \left( {{eq}.\mspace{14mu} 2} \right)\end{matrix}$

where a correlation with the function is at least 0.4, 0.5, 0.6,0.7,0.8, or 0.9, where abs is absorbance of the sample at the givenwavelength, such as approximated by water absorbance at the givenwavelength, and scattering is the scattering coefficient and/or relativescattering coefficient at the given wavelength relative to neighboringwavelengths.

Referring now to FIG. 12 and referring again to FIG. 11B, astep-function bandpass filters is described. In this example, a firststep-function bandpass filter 1140 is illustrated with a large percenttransmittance in the first overtone spectral region 960 and a lowertransmittance, such as about 10, 20, 30, 40, or 50 percenttransmittance, in the second overtone spectral regions 970. A majorbenefit of the first step-function bandpass filter 1140 is simultaneouscollection of light from the first and second overtone spectral regions960, 970, where the lower transmittance of the first overtone region960, relative to the second overtone region 970, is compensated for bythe greater transmittance in the first overtone region 960, relative tothe second overtone region 970, of the first step-function bandpassfilter and the difference in detectivity, D*, between the two regions.As illustrated in FIG. 12, the first step-function bandpass filter isoptionally a combination of a shortpass and longpass filter, such as thesecond shortpass filter 1014 and a fourth longpass filter 918, where thefourth longpass filter 918 intentionally leaks light, such as less than30, 20, 10, or 5 percent, at wavelengths shorter than about 1450 nm.Generally, the step-function bandpass filter has any transmittanceprofile. However, preferably, sections of 25, 50, 100, 200, or morenanometers of the step-function bandpass filter are anti-correlated withwater absorbance, scattering, or a combination thereof, with acorrelation coefficient of less than about −0.9, −0.8, −0.7, or −0.6.

Referring now to FIGS. 13A, 13B, 14A, and 14B, narrowband filters areillustrated relative to absorbance features of blood and/or skinconstituents. In FIG. 13A, a first analyte narrowband bandpass filter isillustrated; overlaid with fat absorbance bands in FIG. 13B. In FIG.14A, a second analyte narrowband bandpass filter is illustrated;overlaid with a glucose absorbance bands in FIG. 14B. Generally, a setof n individual filters, where each filter passes wavelengths dominatedby a limited number of sample constituents, are optionally used.Optionally and preferably the n individual filters are associated withindividual detectors or groups of detectors of the two-dimensionaldetector array 134, as described infra. Notably, since the analytenarrowband filters, such as in FIGS. 13A, 13B, 14A, and 14B, occur atdifferent wavelengths where the total absorbance, dominated by waterabsorbance and/or scattering, varies, preferably the detector array usesdifferent gain settings and/or integration times for different detectorelements, within the two-dimensional detector array 134, associated withdifferent optical filters.

Detector Array/Filter Array Combinations

Referring now to FIG. 15, a detector array/filter array assembly 1500 isillustrated. For clarity of presentation and without limitation, thedetector array/filter array assembly 1500 is illustrated and describedas a single unit. However, optionally, the one or more two-dimensionalfilter arrays are optionally proximate the two-dimensional detectorarray 134, such as within less than 5, 2, 1, or 0.5 millimeters or arewell removed from the two-dimensional detector array 134, such as at anyposition in the optical train between the source system 110 and thedetector system 130. Further, for clarity of presentation and withoutlimitation, two two-dimensional filter arrays are described, which arerepresentative of 1, 2, 3, 4, 5, or more filter arrays. Still further,the two-dimensional filter arrays presented are optionally presented inreverse or any order in the optical train.

Still referring to FIG. 15, a first example of the detector array/filterarray assembly 1500 is described, which is a form of the incidentoptic/two-dimensional array system 700. In this example, thetwo-dimensional detector array 134 is combined with 1, 2, 3, 4 or moretwo-dimensional optical filter arrays, such as a first optical filterarray 1510 and a second optical filter array 1520. Several features ofthe detector array/filter array assembly 1500 are noted.

First, optionally individual detector elements, A, B, C, optically alignwith individual filters of the first optical filter array 1510, i, ii,iii, and/or optically align with individual filters of the secondoptical filter array 1520, 1, 2, 3. Second, optionally two or moredetector elements, D, E, F, optically align with a single filter elementof the first optical filter array 1510, iv, which aligns with two ormore elements of the second optical filter array 1520, 4, 5. Third,optionally, a single optical filter element of the first optical filterarray 1510, iv, optically aligns with two or more elements of the secondoptical filter array 1520, 4, 5. Fourth, optionally, a single opticalfilter element of the second optical filter array 1520, 5, opticallyaligns with two or more elements of the first optical filter array 1520,iv, vi. Fifth, optionally columns and or rows of detector elements, (D,E, F), (F, I, L) align with a column optic, iv, or row optic, 5,respectively. Fifth, a single two-dimensional filter array, such as thefirst two-dimensional optical filter array 1510, optionally contains 2,3, 4, 5, 10, 20, 50, or more filter types. Sixth, a singletwo-dimensional filter array, such as the first two-dimensional opticalfilter array 1510, optionally contains 2, 3, 4, 5, 10, 20, 50, or morefilter shapes.

Referring now to FIG. 16, a multiple illumination zone/multipledetection zone system 1600 is illustrated. For example, an array ofillumination points delivered from the photon transport system 120 isillustrated launching photons out of the page along the x-axis into theskin of the subject 170, not illustrated. An array of detection zonesare achieved, monitoring photons moving into the page along the x-axis,using the two-dimensional detector array 134 and as illustrated theoptional first optical filter array 1510. Similar to the systemsdescribed supra when referring to FIG. 8B, the illustrated illuminationarray optionally illuminates all illuminators; a single illuminator,such as element A, B, or C; and/or subsets of illuminators, such aselements A and B or A, B, and C. As described, supra, the optionallyvarying position of illumination coupled with the two-dimensionaldetector array 134 yields discrete pathlength and depth of penetrationinformation about the optically sampled skin tissue of the subject 170for each detector element of the two-dimensional detector array 134. Asillustrated, the first two-dimensional optical filter array 1510provides additional insight as to the sampled skin by selectivelyfiltering: (1) regions, such as the combination band region 950, thefirst overtone region 960, and/or the second overtone region 970; (2)analytes, such as through use of the narrowband analyte filters; and/or(3) based on intensity of the observed signal, such as throughnarrowband filters designed for a narrow range of absorbances of thesample tissue, where detector gain elements and/or integration times areoptionally individually configured for each element or group ofelements, such as along a column or row, of the two-dimensional detectorarray 134.

Detector

Physical and tissue constraints limit a sample interface size betweenthe analyzer 100 and subject 170. As such, minimizing use of non-opticalparameters in the sample interface is beneficial. In one embodiment, areadout element of a CCD array is place on an outer perimeter of thesample interface area or outside of the perimeter. If two or moredetector arrays are used, the readout elements of the detector arraysare optionally on opposite sides of the sample interface or on adjacentsides of the sample interface, such as at about ninety degrees from eachother. Similarly, if three of more detector arrays are utilized, thereadout positions of the multiple detector arrays optionalcircumferentially surround the sample interface area. Further, havingmultiple detector arrays allows a more rapid readout of the data as thereadouts are optionally at least partially in parallel. Parallel readoutof the gathered signal allows: (1) faster readout, (2) timing of readoutcorresponding to an expected signal-to-noise ratio, and/or (3) anability to start calculations before all data is received, such asinitiation of a tissue-specific tissue map and/or part of a rollingglucose concentration estimation. Still further, columns/rows of atraditional CCD array are optionally configured along arcs, chords,circles, and/or along an arc allowing detector elements to be positionedin concentric rings or other non-rectangular patterns. Still further,optionally the individual rows, columns, and/or curved sets of detectorelements are optionally read out individually allowing an inner set,relative to an illuminator, where absorbance is smallest to be read outfirst and/or more often than outer detector sets, where largerabsorbance of tissue leads to longer sample integration times.

Multiple Two-Dimensional Detector Arrays

Referring now to FIG. 17, a multiple two-dimensional detector arraysystem 1700 is illustrated. As illustrated, the photon transport system120 delivers photons proximate a plurality of two-dimensional detectorarrays denoted here as a first detector array 1702, a second detectorarray 1704, a third detector array 1706, and a fourth detector array1708. Generally, any number of two-dimensional detector arrays areoptionally used, such as 2, 3, 4, 5, 10, 20, or more detector arrays.Configurations of the detector arrays 1702, 1704, 1706, 1708 aredescribed, infra.

Referring still to FIG. 17 and referring now to the first detector array1702, the first detector array is optionally positioned with an edge ofthe first detector array 1702 proximate an outer border or edge of anillumination point, zone, or array of the photon transport system 120.In this example, first detector array 1702 is optically and/orphysically coupled to a series of filters, such as: a first filter, 1,coupled to a first detector element row; a second filter, 2, coupled toa second detector row; a third filter, 3, coupled to a third detectorrow; a fourth filter, 4, coupled to a fourth detector row; and a fifthfilter, L, coupled to a fifth detector row. Here the first, second,third, fourth, and fifth filter, 1, 2, 3, 4, L, are optionally acombination band filter, a first overtone filter, a first and secondovertone filter, a second overtone filter, and luminance filter,respectively. Similarly, the first, second, third, fourth, and fifthfilter, 1, 2, 3, 4, L, are optionally an analyte narrowband bandpassfilter, a spectral region filter, a first overtone filter, a secondnarrowband analyte filter, and luminance filter, respectively.Generally, the individual filters are any optical filter. The individualfilters optionally cover a column, row, geometric sector, and/ortwo-dimensional region of the two-dimensional detector array 134.Optionally, physical edges of the optical filters fall onto unuseddetector elements, such as a column, row, or line of filter elements.

Referring still to FIG. 17 and referring now to the second detectorarray 1704, additional detector/filter configurations are described.First, the second detector array 1704 is optionally positioned with acorner proximate the outer border or edge of an illumination point,zone, or array of the photon transport system 120. Rotation of thesecond detector array 1704 relative to the first detector array 1702yields a second set of distinct pathlengths and correlated depths ofpenetration compared to those observed using the first detector array,as described supra. Second, the same filter elements, as used on thefirst detector array 1702, are optionally used on the second detectorarray 1704, which reduces manufacturing costs and research anddevelopment time understanding finer points, such as temperaturestability of the filters. However, the physical mounting configurationof the filters are optionally different, which yields an additional setof measures of state of the subject 170. For example, the first filter,1, as illustrated is positioned along two diagonals of the seconddetector array 1704, which yields three optical filter/detectorcombinations not observed with the first detector array 1702 where thethree new combinations relate to three additional sampled pathlengthsand depths of penetration of the subject 170. Similarly, the second,third, fourth, and fifth filters, 2, 3, 4, L, are positioned alongdiagonals across the second detector array 1704 yielding, asillustrated, eighteen additional measurements of the state of thesubject 170. Further, in this example, one set of detector elements arenot associated with a filter, which yields yet another set ofmeasurements of the state of the subject 170.

Referring still to FIG. 17 and referring now to the third detector array1706, additional detector/filter configurations are described. First,the first, second, third, and fourth filters, 1, 2, 3, 4, are orientatedin yet another set of configurations relative to the photon transportsystem 120. Notably, in this example, some of the source/detectorelement distances are intentionally redundant yielding internalprecision, outlier, sample inhomogeneity checks, and/or sample interface150 contact checks. For example, three elements of the second and thirddetector array 1704, 1706 have redundant positions of the firstfilter, 1. In addition, one detector element of the third detector array1706 uses the first filter, 1, in a position not used with the first orsecond detector arrays 1702, 1704 yielding yet another measure of thestate of the subject 170. Similarly, the second filter, 2, is configuredwith both redundant positions, relative to those used with the seconddetector array 1704, and with new positions, relative to those used withthe second detector array 1704. In this example, the third filter andfourth filter, 3, 4, are configured at larger distances from a meanpoint of the illumination zone relative to the filter positionsconfigurations of the second detector array 1704. In practice, some ofthe third and fourth filter/detector positions are optimally probing theglucose containing dermal region 174, while others will yieldinformation on the intervening and underlying epidermis and subcutaneousfat regions, respectively. Generally, the range of information gatheredis used in post-processing to generate more accurate and precise analyteconcentration information, such as through development and use of thesame data used to form a person specific tissue map.

Referring still to FIG. 17 and referring now to the fourth detectorarray 1708, still additional detector/filter configurations aredescribed. In this example, still further illumination zone to detectionzone distances are illustrated for the first, second, and third filters,1, 2, 3. As illustrated, the second and third filters, 2, 3, such as afirst overtone and a second overtone filter, extend to still greaterradial distances from the illumination zone yielding still yet anotherset of measures of the state of the subject 170. Further, in thisexample, the fourth detector array 1708 is rotated to a non-symmetricorientation relative to the illumination zone, which yields an entirelynew set of pathlengths and depths of penetration, as described supra.

Referring still to FIG. 17, for clarity of presentation and withoutlimitation a particular filter/detector combination of the first filter,1, is described. Here the first filter, 1, is a combination band filterused for short distances between the illumination zone and detectionzone. As described supra in the description of the first, second, third,and fourth detector arrays 1702, 1704, 1706, 1708 multiple shortdistances between the illumination zone and detection zone are probed,some of which will optimally probe the glucose containing dermal layer174 of the subject 170, some of which will primarily probe the epidermis173 of the subject 170, and some of which probe into the subcutaneousfat layer 176 of the subject 170. The availability of multiple measuresof the state of the subject allows post-processing to derive informationabout the tissue layer thicknesses, tissue homogeneity, probedpathlengths, probed tissue depth, and/or analyte concentration of thesubject 170 with optional use of redundant information, exclusion ofoutlier information, exclusion of non-optimally sampled tissue, and/orinclusion of optimally measured tissue. Similarly, use of the second,third, fourth, and fifth filter, 2, 3, 4, L, along with use of no filterat a variety of intelligently selected radial distances from theillumination zone based on scattering and absorbance properties of thetissue of the subject 170 yield additional complementary and optionallysimultaneous information on the state of the subject 170.

Referring still to FIG. 17, for clarity and without loss ofgeneralization another example of the photon transport system 120delivering light to the skin of the subject 170 at multiple illuminationpositions relative to two or more detector arrays is provided. In thisexample, the first detector array 1702 is illustrated with a pluralityof filters along rows of detector elements. For example, a first filter,illustrated as filter 1, is optionally a combination band filter; asecond filter, illustrated as filter 2, is optionally a first overtonefilter; a third filter, illustrated as filter 3, is optionally a firstand second overtone filter; a fourth filter, illustrated as filter 4, isoptionally a second overtone filter; and a fifth filter, illustrated asfilter L, is optionally a luminance filter/intensity filter. Theinventor notes that the filters are arranged in readily manufacturedrows, provide a spread of radial distances within a row, and fall in anorder of wavelength inversely correlating with mean pathlength as afunction of radial distance from the illuminator. Referring now to thesecond detector array 1704, the third detector array 1706, and thefourth detector array 1708 positioned about the illumination zone fromthe photon transport system 120, the inventor notes that the same fivefilters positioned in different configurations and/or orders as afunction of radial distance from the illumination zone and/or as afunction of rotation angle of the detector array yield a plurality ofadditional pathlengths. For brevity and clarity of presentation, onlythe first filter, filter 1, is addressed. In the first detector array1702, the first filter represents three distinct mean pathlengths from amean illumination zone using the 1^(st) and 5^(th) detector elements,the 2^(nd) and 4^(th) detector elements, and the 3^(rd) detectorelement. Similarly, the second detector array filter 1704 monitors twoadditional mean pathlengths from the mean illumination zone using thefirst filter and individual detector elements. The third detector array1706 could measure the same mean pathlengths as the second detectorarray 1704; however, preferably the third detector array 1706 measuresstill two more mean pathlengths using two pairs of detector elementswith differing distances from the mean illumination zone. Similarly, thefourth detector array 1708 optionally measures a number of yet stillfurther distinct mean pathlengths, such as by binning all six detectorelements, or by binning rows of detector elements. Thus, at a firstpoint in time, the four detector arrays 1702, 1704, 1706, 1708optionally monitor at least eight mean pathlengths using only the firstfilter. At a second point in time, an additional distinct eightpathlengths are optionally monitored by illuminating a second pattern ofthe illustrated illumination points. The inventor notes that evenilluminating all of the illumination points or only the first and secondrings of illumination points, despite having the same mean point ofillumination, will yield eight additional mean pathlengths in the tissuedue to tissue inhomogeneity. Clearly, simultaneous use of the other fourfilters allows for simultaneous collections of spectra having at leastforty pathlengths (8×5). Further, filter 1, is optionally different, interms of a filter parameter such as a cut-on wavelength or a cut-offwavelength, for each detector array 1702, 1704, 1706, 1708 withoutcomplicating manufacturing, which yields still additional simultaneouslyprobed optical tissue pathlengths. Generally, any number or detectorelements, any number of detector arrays, any number of filters, and/orany geometry of filter layout are optionally used to obtain a desirednumber of simultaneously probed sample pathlengths. Optionally, signalfrom groups of common detector elements are binned to enhance a givensignal-to-noise ratio.

Further, the two-dimensional detector arrays described herein optionallycontain 1, 2, 3, or more detector materials 134 and/or types. Forexample, a single two-dimensional detector array 134 optionally contains1.7, 1.9, 2.2, and/or 2.6 μm indium/gallium/arsenide detectors. Forexample, the 2.6 micrometer indium/gallium/arsenide detector isoptionally optically coupled with longpass, shortpass and/or bandpassfilters for the combination band 950 spectral region and/or the 1.7,1.9, 2.2 μm indium/gallium/arsenide detectors are optionally coupledwith longpass, shortpass, and/or bandpass filters for the first overtoneregion 960. Optionally and preferably, different detector types arejoined along a joint and/or a seal, where the seal optionallycorresponds with a joint or seal between two filter types or simply aset, such as a column, of unused detector elements.

Referring now to FIG. 18A, a multiple detector array system 1800 isdescribed, which is a further example of a multiple two-dimensionaldetector array system. In this example, multiple detector types areoptionally used, as described infra. Further, in this example, multipledetector sizes are optionally used, as described infra.

Referring still to FIG. 18A, additional examples of two-dimensionaldetector/filter arrays are provided. Referring now to the first detectorarray 1702 and the second detector array 1704, the second detector array1704 relative to the first detector array illustrates:

-   -   that two detector arrays optionally vary in length and/or width        by at least 5, 10, or 20 percent, which results in an ability to        miniaturize a sample probe head and/or to enhance collection        efficiency of delivered photons by increasing overall skin        surface coverage by the detectors; and    -   that the row and/or columns of detector elements optionally have        different single element sizes, which allows control over range        of pathlengths monitored with a given detector element.

Referring now to the third detector array 1706, the two-dimensionaldetector array 134 optionally contains sensors and/or optics to measurea range of parameters, such as a local tissue temperature, T₁, a localtissue pressure, P₁, and/or a local illumination, I₁. Referring now tothe fourth detector array 1708, the two-dimensional detector array 134is optionally designed to be read out in columns or sideways as rows,which allows each row to have a different detector element size.Increasing the detector element size as a function of radial distanceaway from an illuminator allows an enhanced/tuned signal-to-noise ratioas the detector aperture is larger as the number of photons exiting theskin with increased radial distance decreases. The larger aperture sizesof the detectors enhances signal-to-noise ratios as baseline noiseremains constant and thermal noise increases at a smaller, less thanlinear, rate compared to the linear increase in signal with increasedintegration time. Referring now to the first through fourth detectorarrays 1702, 1704, 1706, 1708, an optional range of illuminator/detectorgaps are illustrated 121, 123, 125, 127 for the first through fourthdetector arrays 1702, 1704, 1706, 1708, respectively.

Referring now to FIG. 18B, yet another example of a multipletwo-dimensional detector/filter array system is provided. In thisexample, a first detector array 1702 is configured with zones ofregularly shaped filters over multiple individual detector elementsizes. For example, the first filter, 1, such as a first overtonefilter, covers two rows of detector elements, which aids in filtercosts, alignment, masks, and/or installation. The first row of detectorelements comprises smaller dimensions than the second row of detectorelements, which enhances signal-to-noise ratios in each row as the timeto fill detector wells in the first row of detector elements is lessthan the time to fill detector wells in the second row of detectorelements due to the light transport/scattering properties in the 1450 to1900 nm spectral region. The larger aperture of the second row detectorelements gathers more light as a function of time compared to the firstrow detector elements as an area of a detector element in the second rowis at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times larger than an area of adetector element in the first row. Similarly, the third and fourth rowsof detector elements are optionally associated with the second optic, 2,such as the first overtone/second overtone band filter. The third row ofdetector elements are larger than the first row of detector elements dueto fewer photons from an illumination zone exiting the skin at greaterdistances from the illumination zone and smaller than the second row ofdetector elements due to the enlarged spectral bandwidth of the firstovertone/second overtone band filter. The fifth row of detector elementsoptionally uses a third, 3, filter, such as a second overtone filter.Generally, the area of detector elements is preferably manufactured toinversely match light density exiting the skin of the subject 170 ineach optically filtered wavelength range. Here, the first detector array1702 in this example is designed to optionally readout in rows, whichallows different rows to comprise different sizes of detector elements.Optionally, filters at one or more detector elements positions arematched to wavelengths of an LED of a set of LEDs.

Referring still to FIG. 18B, a second detector array 1704 is presentedin a rotated configuration about the x-axis relative to the firstdetector array 1702. The rotation of the second detector array 1704yields a continuum of pathlength ranges for a row of detectors. Forexample, in the first detector array 1702, the first row of detectorsmonitor four average pathlengths of illuminated tissue due to C2symmetry of the detector elements in the first row, where for examplethe inner two detector elements observe a single first mean pathlengthand the outer two detector elements observe a single second meanpathlength. However, in stark contrast, the first row of detectorelements in the second detector/filter array 1704 monitor eightdifferent mean optical pathlengths of light delivered by the photontransport system 120. Similarly, each row of detector elements in thesecond detector array 1704 observe, simultaneously, more meanpathlengths of photons from the photon transport system 120 compared toa corresponding row of detector elements in the first detector array1702 due to the rotation of the second detector array in the y,z-planerelative to a line from a center of the second detector array to acenter of the illumination zone.

Detector Array/Guiding Optical Array Combinations

Referring now to FIG. 19A and FIG. 19B, a two-dimensional detectorarray/guiding optic array assembly 1900 is illustrated proximate outputof the photon transport system 120, illustrated as an array of incidentlight optics proximate skin tissue, where the skin is not illustrated.For clarity of presentation and without limitation, the detectorarray/guiding optic array assembly 1900 is illustrated and described asa single assembled detector/optic unit 1930. However, optionally, thetwo-dimensional guiding optic array 1920 is optionally proximate thetwo-dimensional detector array 134, such as within less than 20, 10, 5,2, 1, or 0.5 millimeters or is well removed from the two-dimensionaldetector array 134, such as at any position in the optical train betweenthe skin of the subject 170 and the detector system 130. Further, thetwo-dimensional guiding optic arrays is optionally on either opticaltrain side of one or more of the optional two-dimensional filter arrays.

Still referring to FIGS. 19A and FIG. 19B, varying optional detectorshape/optical filter combinations are described.

In a first case, two or more detector elements of the two-dimensionaldetector array 134 are optically coupled with a single optic. Forexample, the first column of detectors in the two-dimensional detectorarray 134 are coupled with a single optic, O₁. The single optic, O₁, isoptionally a pathlength extending optic, which redirects light toinclude a vector component back toward the illumination zone resultingin a longer mean pathlength and/or depth of penetration. The pathlengthextending optic is optionally and preferably used close to theillumination zone, in this case to the left of thetwo-dimensional/guiding optic array assembly 1900, to yield additionalphotons in sampling the dermis region and fewer photons sampling solelythe epidermis region, as described supra in relation to FIG. 7A. Theextending optic is particularly useful with a combination bandsource/combination band filter/detector combination.

In a second case, 1, 2, 3, 4, or more individual detector elements ofthe two-dimensional detector array 134 are optionally each opticallycoupled with discrete individual optics of the two-dimensional opticarray 1920. For example, as illustrated, the second column of detectorscomprise combination band detectors, C_(2(a-f)), each coupled withstandard focusing optics and/or optics redirecting light to comprise avector back toward the mean radial axis of detected incident photons,C_(2b,2e). Optionally, the further from the mean radial axis of thedetected incident photons, the greater the magnitude of the inducedvector component redirecting photons back toward the mean radial axis,C_(2a,2f).

In a third case, light gathering areas of individual optics in thetwo-dimensional optic array 1920 are optionally larger with increasingdistance from an illumination zone proximate incident light enteringskin of the subject 170 from the photon transport system 120. Forexample a sixth optic, O₆, optionally has a larger surface area alongthe y/z-plane compared to a fourth optic, O₄, which has a larger areathan a third optic, O₃, which has a larger area than a second optic,O_(2a). For a noninvasive near-infrared spectral measurement, thegenerally, but not absolutely, larger collection areas as a function ofradial distance from the illumination zone aid signal-to-noise ratiosdue to fewer photons reaching the larger radial distances. The opticsize matched to spectral region is further described, infra.

In a fourth case, light gathering areas along the y/z-plane are chosento enhance signal-to-noise ratios for varying spectral regions, such asthe combination band region 950, the first overtone region 960, thesecond overtone region 970, and/or one or more narrowband analytespecific regions. For example, observed light intensity generallydecreases with increased radial distance from an illumination zone inthe spectral region of 1100 to 2500 nm. Further, the radial distanceneeded to obtain quality/high signal-to-noise ratio spectra using dermallayer probing photons generally varies with radial distance from theillumination zone. The inventor has determined that a series of detectortypes, optical filters, and/or light gathering areas are preferentiallyused, such as: a combination band region detector, C_(2a), at closeradial distance to the source with a first optic collection area,O_(2a); a first overtone detector, 1, at an intermediate radial distanceto the source with a second optic collection area, O₃; a first andsecond overtone detector, 1 and 2, at a still further radial distancefrom the illumination zone with a third collection optic area, O₄;and/or a second overtone detector, 2, at a yet still further radialdistance from the illumination zone with a fourth optic collection area,O₆.

In a fifth case, the two-dimensional detector area 134 contains agreater or first number of detector elements in a given area at a firstradial distance from the illumination zone and a lesser or second numberof detector elements in a second equally sized area at a second greaterradial distance from the illumination zone. For example, the firstnumber of detector elements is optionally 10, 20, 30, 40, 50, 100, 150,200, or more percent larger than the second number of detector elements.

In a sixth case, more than one optic size, in the y/z-plane is used fora single column or row of detector elements of the two-dimensionaldetector array 134, such as the fourth and fifth optic, O₄ and O₅,associated with the fourth detector column in the provided example.

In a seventh case, one or more filters are optically coupled to one ormore corresponding elements of the two-dimensional detector array 132and/or to one or more corresponding elements of the two-dimensionaloptic array 1920.

In an eighth case, one or more detector elements of the two-dimensionaldetector array are optically coupled to one or more luminance filters.

Two-Dimensional Detector/Optical Filter/Guiding Optic Combinations

Referring now to FIGS. 20(A&B) and FIGS. 21(A&B), various exemplarycombinations of the two-dimensional detector array 134/thetwo-dimensional filter array 1510/two-dimensional optic array 1920 areprovided. Herein, examples are provided for clarity of presentation andwithout limitation. Generally, the examples represent any combinationand/or permutation of the two-dimensional detector array 134, thetwo-dimensional filter array 1510, and/or the two-dimensional opticarray 1920. Further, for clarity of presentation and without limitation,the two-dimensional filter array 1510 is depicted as two optionalarrays, a two-dimensional longpass filter array 1512 and atwo-dimensional shortpass filter array 1514. Still further, thetwo-dimensional detector array 134, the two-dimensional longpass filterarray 1512, the two-dimensional shortpass filter array 1514, and thetwo-dimensional optic array 1920 are optionally individually spaced fromone another, are optionally contacting each other as in adetector/filter/optic assembly 2050, and/or have gaps between one ormore of the individual two-dimensional arrays.

Referring now to FIG. 20A and FIG. 20B, a first example of atwo-dimensional detector/filter/optic system 2000 is described. In thisfirst example, the two-dimensional detector array 134 contains aplurality of detectors in any geometric pattern, of one or more sizes.Further, the optional two-dimensional filter array 1510 is depicted aslayers of longpass filter elements and/or shortpass filter elements,such as the two-dimensional longpass filter array 1512 and/or thetwo-dimensional shortpass filter array 1514. The two-dimensionallongpass filter array 1512 is optionally 1, 2, 3, or more filter types,LP₁, LP₂, LP₃. Similarly, the two-dimensional shortpass filter array1514 is optionally 1, 2, 3, or more filter types, SP₁, SP₂, SP₃.Optionally, elements of the two-dimensional shortpass filter array 1514are present in the two-dimensional longpass filter array 1512 andvise-versa. Still further, the optional two-dimensional optic layer 1920contains 1, 2, 3, or more optic sizes and/or types, O₁, O₂, O₃.Optionally, one or more of the longpass and/or shortpass filters overlapone or more detectors or optics of the two-dimensional detector array132 and two-dimensional optic array 1920, respectively. Optionally, oneor more edges of a longpass filter element of the two-dimensionallongpass filter array 1512 do not align with one or more edges of ashortpass filter of the two-dimensional shortpass filter array 1514 orvise-versa. Generally, multiple configurations of the two-dimensionaldetector/filter/optic system 2000 are useful in a noninvasive analyteconcentration determination, such as a noninvasive spectraldetermination of glucose concentration. One exemplary configuration isprovided, infra.

Referring now to FIG. 21A and FIG. 21B, a second example of thetwo-dimensional detector/filter/optic system 2000 is described. In thissecond example, for clarity of presentation particular detector types,filter parameters, spectral regions, and/or optics are described thatare representative of many possible detector, filter, and/or opticalconfigurations. In this second example, filters and optics for varyingspectral regions are provided in Table 1.

TABLE 1 Simultaneous Multiple Region Analysis Long- Short- pass passDetector Filter Filter Detector(s) Type* (μm) (μm) Optic Region 1-6 2.51.9 2.5 Pathlength Combination Extending Band  7-12 2.5 1.9 2.5 StandardCombination Band 13-15 2.5 1.9 2.5 Focusing Combination Band 16 2.5 1.42.5 Focusing Combination Band and 1^(st) Overtone 17 1.9 1.4 1.9Focusing 1^(st) Overtone 18 1.9 1.0 1.9 Focusing 1^(st) and 2^(nd)Overtone 19 2.5 1.0 2.5 Pathlength Broadband Reducing 20 1.9 1.0 1.9Pathlength 1^(st) and 2^(nd) Reducing Overtone 21 1.7 1.0 1.4 Pathlength2^(nd) Overtone Reducing *non-limiting examples of InGaAs detectorcut-off wavelengths

From Table 1, it is observed that optionally multiple spectral regionsare simultaneously observed with a single two-dimensional detectorarray. It is further noted that observed mean sampled pathlengths andobserved mean sampled depths of penetration correspond with filter typeschanging as a function of relative radial distance from an illuminationzone; the illumination zone to the left of the illustratedtwo-dimensional detector and associated optics. Still further, ifadditional emphasis is desired for a particular spectral region, moredetectors are simply used with the appropriate filter combination. Forexample, if more first overtone spectra are desired, the area of opticsassociated with detector 17 is optionally expanded along the y-axis forsimilar pathlengths and/or along the z-axis for longer and/or shortermean pathlengths.

Multiple combinations of filter types and/or optic types are optionallyused in the noninvasive analyte spectral determination process. Table 2shows an exemplary configuration for a noninvasive analysis performedusing the first overtone 960 and second overtone 970 spectral regions.From Table 2, it is again observed that, optionally, multiple spectralregions are simultaneously observed with a single two-dimensionaldetector array optically coupled to an array of filter types and/or anarray of light directing optics.

TABLE 2 Simultaneous Multiple Region Analysis Long- Short- pass passDetector Filter Filter Column (μm) (μm) Optic Region 1 1.4 1.9Pathlength First Overtone Extending 2 1.6 1.4 Standard Analyte Band 31.4 1.9 Focusing First Overtone 4 1.6 1.4 Focusing Analyte Band 5 1.11.9 Standard 1^(st) and 2^(nd) Overtone 6 1.1 1.9 Focusing 1^(st) and2^(nd) Overtone 7 1.0 1.7 Focusing Extended 2^(nd) Overtone 8 1.0 1.4Focusing 2^(nd) Overtone 9 1.0 1.4 Pathlength 2^(nd) Overtone Reducing

Temporal Resolution

The second method of temporal resolution is optionally performed in anumber of manners. For clarity of presentation and without limitation, atemporal resolution example is provided where photons are timed using agating system and the elapsed time is used to determine photon paths intissue.

Referring now to FIGS. 22(A-D), an example of a temporally resolvedgating system 2200 is illustrated. Generally, in the temporal gatingsystem 2200 the time of flight of a photon is used to determine thepathlength, b. Referring now to FIG. 22A, at an initial time, t₀, aninterrogation pulse 2210 of one or more photons is introduced to thesample, which herein is skin of the subject 170. The interrogation pulse2210 is also referred to as a pump pulse or as a flash of light. At oneor more subsequent gated detection times 2220, after passing through thesample the interrogation pulse 2210 is detected. As illustrated, thegated detection times are at a first time 2222, t₁; a second time 2224,t₂; a third time 2226, t₃; and at an n^(th) time 2228, t_(n), where n isa positive number. Optionally, the gated detection times 2220 overlap.For the near-infrared spectral region, the elapsed time used to detectthe interrogation photons 2210 is on the order of picoseconds, such asless than about 100, 10, or 1 picosecond. The physical pathlength, b, isdetermined using equation 2:

$\begin{matrix}{{OPD} = {\frac{c}{n}(b)}} & \left( {{eq}.\mspace{14mu} 2} \right)\end{matrix}$

where OPD is the optical path distance, c is the speed of light, n isthe index of refraction of the sample, and b is the physical pathlength.Optionally, n is a mathematical representation of a series of indices ofrefraction of various constituents of skin and/or skin and surroundingtissue layers. More generally, observed pathlength is related to elapsedtime between photon launch and photon detection where the pathlength ofphotons in the sample is related to elapsed time, optionally with one ormore additional variables related to one or more refractive indices.

Referring now to FIG. 22B, illustrative paths of the photons for thefirst gated detection time 2222 are provided. A first path, p_(1a);second path, p_(1b); and third path, p_(1c), of photons in the tissueare illustrated. In each case, the total pathlength, for a constantindex of refraction, is the same for each path. However, the probabilityof each path also depends on the anisotropy of the tissue and thevariable indices of refraction of traversed tissue voxels.

Referring now to FIG. 22C, illustrative paths of the photons for thesecond gated detection time 2224 are provided. A first path, p_(2a);second path, p_(2b); and third path, p_(2c), of photons in the tissueare illustrated. Again, in each case the total pathlength for the secondelapsed time, t₂, is the same for each path. Generally, if the delay tothe second gated detection time 2224 is twice as long as the first gateddetection time 2222, then the second pathlength, p₂, for the secondgated detection time 2224 is twice as long as the first pathlength, p₁,for the first gated detection time 2222. Knowledge of anisotropy isoptionally used to decrease the probability spread of paths observed inthe second set of pathlengths, p_(2a), p_(2b), p_(2c). Similarlya-priori knowledge of approximate physiological thickness of varyingtissue layers, such as an epidermal thickness of a patient, an averageepidermal thickness of a population, a dermal thickness of a patient,and/or an average dermal thickness of a population is optionally used toreduce error in an estimation of pathlength, a product of pathlength anda molar absorptivity, and/or a glucose concentration by limiting boundsof probability of a photon traversing different pathways through theskin layers and still returning to the detection element with theelapsed time. Similarly, knowledge of an index of refraction of one ormore sample constituents and/or a mathematical representation ofprobable indices of refraction is also optionally used to reduce errorin estimation of a pathlength, molar absorptivity, and/or an analyteproperty concentration estimation. Still further, knowledge of anincident point or region of light entering she skin of the subjectrelative to a detection zone is optionally used to further determineprobability of a photon traversing dermal or subcutaneous fat layersalong with bounding errors of pathlength in each layer.

Referring now to FIG. 22D, mean pathlengths and trajectories areillustrated for three elapsed times, t₁, t₂, t₃. As with the spatiallyresolved method, generally, for photons in the near-infrared region from1100 to 2500 nanometers, both a mean depth of penetration of thephotons, d_(n); the total radial distance traveled, r_(m); and the totaloptical pathlength increases with increasing time, where the fiberoptic-to-detector distance is less than about three millimeters.Preferably, elapsed times between a pulse of incident photon deliveryand time gated detection are in a range between 100 nanoseconds and 100picoseconds, such as about 1, 5, 10, and 50 picoseconds.

Spatial and Temporal Resolution

Hence, both the spatial resolution method and temporal resolution methodyield information on pathlength, b, which is optionally used by the dataprocessing system 140 to reduce error in the determined concentration,C.

Analyzer and Subject Variation

As described, supra, Beer's Law states that absorbance, A, isproportional to pathlength, b, times concentration, C. More precisely,Beer's Law includes a molar absorbance, E, term, as shown in equation 3:

A=εbC   (eq. 3)

Typically, spectroscopists consider the molar absorbance as a constantdue to the difficulties in determination of the molar absorbance for acomplex sample, such as skin of the subject 170. However, informationrelated to the combined molar absorbance and pathlength product for skintissue of individuals is optionally determined using one or both of thespatially resolved method and time resolved method, described supra. Inthe field of noninvasive glucose concentration determination, theproduct of molar absorbance and pathlength relates at least to thedermal thickness of the particular individual or subject 170 beinganalyzed. Examples of spatially resolved analyzer methods used toprovide information on the molar absorbance and/or pathlength usable inreduction of analyte property estimation and/or uncertaintydetermination are provided infra.

Spatially Resolved Analyzer

Herein, an analyzer 100 using fiber optics is used to describe obtainingspatially resolved information, such as pathlength and/or molarabsorbance, of skin of an individual, which is subsequently used by thedata processing system 140. The use of fiber optics in the examples isused without limitation, without loss of generality, and for clarity ofpresentation. More generally, photons are delivered in quantities of oneor more through free space, through optics, and/or off of reflectors tothe skin of the subject 170 as a function of distance from a detectionzone.

Referring again to FIG. 1 and referring now to FIG. 23A, an example of afiber optic interface system 2300 of the analyzer 100 to the subject 170is provided, which is an example of the sample interface system 150.Light from the source system 110 of the analyzer 100 is coupled into afiber optic illumination bundle 2314 of a fiber optic bundle 2310. Thefiber optic illumination bundle 2314 guides light to a sample site 178of the subject 170. The sample site 178 has a surface area and a samplevolume. In a first case, a sample interface tip 2316 of the fiber opticbundle 2310 contacts the subject 170 at the sample site 178. In a secondcase, the sample interface tip 2316 of the fiber optic bundle 2310proximately contacts the subject 170 at the sample site 178, but leavesa sample interface gap 2320 between the sample interface tip 2316 of thefiber optic bundle 2310 and the subject 170. In one instance, the sampleinterface gap 2320 is filled with a contact fluid and/or an opticalcontact fluid. In a second instance, the sample interface gap 2320 isfilled with air, such as atmospheric air. Light transported by the fiberoptic bundle 2310 to the subject 170 interacts with tissue of thesubject 170 at the sample site 178. A portion of the light interactingwith the sample site is collected with one or more fiber opticcollection fibers 2318, which is optionally and preferably integratedinto the fiber optic bundle 2310. As illustrated, a single collectionfiber 2318 is used. The collection fiber 2318 transports collected lightto the detector 132 of the detection system 130.

Referring now to FIG. 23B, a first example of a sample side lightcollection end 2316 of the fiber optic bundle 2310 is illustrated. Inthis example, the single collection fiber 2318 is circumferentiallysurrounded by an optional spacer 2330, where the spacer has an averageradial width of less than about 200, 150, 100, 50, or 25 micrometers.The optional spacer 2330 is circumferentially surrounded by a set offiber optic elements 2313. As illustrated, the set of fiber opticelements 2313 are arranged into a set of radial dispersed fiber opticrings, such as a first ring 2341, a second ring 2342, a third ring 2343,a fourth ring 2344, and an n^(th) ring 2345, where n comprises apositive integer of at least 2, 3, 4, 5, 6, 7, 8, 9, or 10. Optionally,the fiber optic elements 2313 are in any configuration, such as in aclose-packed configuration about the collection fiber 2318 or in anabout close-packed configuration about the collection fiber 2318. Thedistance of each individual fiber optic of the set of fiber opticelements 2313, or light collection element, from the center of thecollection fiber 2318 is preferably known.

Referring now to FIG. 23C, a second example of the sample side lightcollection end 2316 of the fiber optic bundle 2310 is provided. In thisexample, the centrally positioned collection fiber 2318 iscircumferentially surrounded by a set of spacer fibers 2350. The spacerfibers combine to cover a radial distance from the outside of thecollection fiber of less than about 300, 200, 150, 100, 75, 60, 50, or40 micrometers. The spacer fibers 2350 are circumferentially surroundedby the radially dispersed fiber optic rings, such as the first ring2341, the second ring 2342, the third ring 2343, the fourth ring 2344,and the n^(th) ring 2345. Optionally, fiber diameters of the spacerfibers 2350 are at least ten, twenty, or thirty percent larger orsmaller than fiber diameters of the set of fiber optic elements 2313.Further, optionally the fiber optic elements 2313 are arranged in anyspatial configuration radially outward from the spacer fibers 2350. Moregenerally, the set of fiber optic elements 2313 and/or spacer fibers2350 optionally contain two, three, four, or more fiber optic diameters,such as any of about 40, 50, 60, 80, 100, 150, 200, or more micrometers.Optionally, smaller diameter fiber optics, or light collection optics,are positioned closer to any detection fiber and progressively largerdiameter fiber optics are positioned, relative to the smaller diameterfiber optics, further from the detection fiber.

Radial Distribution System

Referring now to FIG. 24A, FIG. 24B, FIG. 25, and FIGS. 26 A-D a systemfor spatial illumination 2400 of the sample site 178 of the subject 170is provided. The spatial illumination system 2400 is used to controldistances between illumination zones and detection zones as a functionof time. In a first case, light is distributed radially relative to adetection zone using a fiber optic bundle. In a second case, light isdistributed radially relative to a detection zone using a reflectiveoptic system and/or a lens system. Generally, the first case and secondcase are non-limiting examples of radial distribution of light about oneor more detection zones as a function of time.

Radial Position Using Fiber Optics

Referring now to FIG. 24A, a third example of the sample side lightcollection end 2316 of the fiber optic bundle 2310 is provided. In thisexample, the collection fiber 2318 or collection optic iscircumferentially surrounded by the set of fiber optic elements 2313 orirradiation points on the skin of the subject 170. For clarity ofpresentation and without loss of generality, the fiber optic elements2313 are depicted in a set of rings radially distributed from thecollection fiber 2318. However, it is understood that the set of fiberoptics 2313 are optionally close packed, arranged in a randomconfiguration, or arranged according to any criterion. Notably, thedistance of each fiber optic element of the set of fiber optic elements2313 from the collection fiber 2318 is optionally determined usingstandard measurement techniques through use of an algorithm and/orthrough use of a dynamically adjustable optic used to deliver light tothe sample, such as through air. Hence, the radial distributionapproach, described infra, is optionally used for individual fiber opticelements and/or groups of fiber optic elements arranged in anyconfiguration. More generally, the radial distribution approach,described infra, is optionally used for any set of illuminationzone/detection zone distances using any form of illuminator and any formof detection system, such as through use of the spatially resolvedsystem and/or the time resolved system.

Referring now to FIG. 24B, an example of a light input end 2312 of thefiber optic bundle 2310 is provided. In this example, individual fibersof the set of fiber optics 2313 having the same or closely spaced radialdistances from the collection fiber 2318 are grouped into a set of fiberoptic bundles or a set of fiber optic bundlets 2410. As illustrated, theseven fibers in the first ring circumferentially surrounding thecollection fiber 2318 are grouped into a first bundlet 2411. Similarly,the sixteen fibers in the second ring circumferentially surrounding thecollection fiber 2318 are grouped into a second bundlet 2412. Similarly,the fibers from the third, fourth, fifth, and sixth rings about thecollection fiber 2318 at the sample side illumination end 2316 of thefiber bundle 2310 are grouped into a third bundlet 2413, a fourthbundlet 2414, a fifth bundlet 2415, and a sixth bundlet 2416,respectively. For clarity of presentation, the individual fibers are notillustrated in the second, third, fourth, fifth, and sixth bundlets2412, 2413, 2414, 2415, 2416. Individual bundles and/or individualfibers of the set of fiber optic bundlets 2410 are optionallyselectively illuminated using a mask 2420, described infra.

Referring now to FIG. 25 and FIG. 23A, a mask wheel 2430 is illustrated.Generally, the mask wheel 2430 rotates, such as through use of a wheelmotor 2420. As a function of mask wheel rotation position, holes orapertures through the mask wheel 2430 selectively pass light from thesource system 110 to the fiber optic input end 2312 of the fiber opticbundle 2310. In practice, the apertures through the mask wheel areprecisely located to align with (1) individual fiber optic elements ofthe set of fiber optics at the input end 2312 of the fiber optic bundleor (2) individual bundlets of the set of fiber optic bundlets 2410.Optionally an encoder or marker section 2440 of the mask wheel 2430 isused for tracking, determining, and/or validating wheel position in use.

Still referring to FIG. 25, an example of use of the mask wheel 2430 toselectively illuminate individual bundlets of the set of fiber opticbundlets 2410 is provided. Herein, for clarity of presentation theindividual bundlets are each presented as uniform size, are exaggeratedin size, and are repositioned on the wheel. For example, as illustrateda first mask position, p₁, 2421 is illustrated at about the seveno'clock position. The first mask position 2421 figuratively illustratesan aperture passing light from the source system 110 to the firstbundlet 2411 while blocking light to the second through sixth bundlets2412-2416. At a second point in time, the mask wheel 2430 is rotatedsuch that a second mask position, p₂, 2422 is aligned with the input end2312 of the fiber optic bundle 2310. As illustrated, at the second pointin time, the mask wheel 2430 passes light from the illumination system110 to the second bundlet 2412, while blocking light to the firstbundlet 2411 and blocking light to the third through six bundlets2413-2416. Similarly, at a third point in time the mask wheel uses athird mask position, p₃, 2423 to selectively pass light into only thefifth bundlet 2415. Similarly, at a fourth point in time the mask wheeluses a fourth mask position, p₄, 2424 to selectively pass light intoonly the sixth bundlet 2416.

Still referring to FIG. 25, thus far the immediately prior example hasonly shown individual illuminated bundlets as a function of time.However, combinations of bundlets are optionally illuminated as afunction of time. In this continuing example, at a fifth point in time,the mask wheel 2430 is rotated such that a fifth mask position, p₅, 2425is aligned with the input end 2312 of the fiber optic bundle 2310. Asillustrated, at the fifth point in time, the mask wheel 1130 passeslight from the illumination system 110 to all of (1) the second bundlet2412, (2) the third bundlet 2413, and (3) the fourth bundlet 2414, whileblocking light to all of (1) the first bundlet 2411, (2) the fifthbundlet 2415, and (3) the sixth bundlet 2416. Similarly, at a sixthpoint in time a sixth mask position, p₆, 2426 of the mask wheel 2430passes light to the second through fifth bundlets 2412-2415 whileblocking light to both the first bundlet 2411 and sixth bundlet 2416.

In practice, the mask wheel 2430 contains an integral number of npositions, where the n positions selectively illuminate and/or block anycombination of: (1) the individual fibers of the set of fiber optics2313 and/or (2) bundlets 2410 of the set of fiber optic optics 2313.Further, the filter wheel is optionally of any shape and uses any numberof motors to position mask position openings relative to selected fiberoptics. Still further, in practice the filter wheel is optionally anyelectro-mechanical and/or electro-optical system used to selectivelyilluminate the individual fibers of the set of fiber optics 2313. Yetstill further, in practice the filter wheel is optionally anyillumination system that selectively passes light to any illuminationoptic or illumination zone, where various illumination zones illuminatevarious regions of the subject 170 as a function of time. The variousillumination zones alter the effectively probed sample site 178 orregion of the subject 170.

Radial Position Using a Mirror and/or Lens System

Referring now to FIGS. 26(A-D), a dynamically positioned optic system2300 for directing incident light to a radially changing position abouta collection zone is provided.

Referring now to FIG. 26A, a mirror 2610 is illustrative of any mirror,lens, mirror system, and/or lens system used to dynamically andpositionally direct incident light to one or more illumination zones ofthe subject 170 relative to one or more detection zones and/or volumesmonitored by the photon transport system 120 and/or the detector system130.

Still more generally, the data processing system 140 and/or the systemcontroller 180 optionally control one or more optics, figurativelyillustrated as the mirror 2310, to dynamically control incident light2311 on the subject 170 relative to a detection zone on the subject 170that combine to form the sample site 178 through control of one or moreof:

-   -   x-axis position of the incident light on the subject 170;    -   y-axis position of the incident light on the subject 170;    -   solid angle of the incident light on a single fiber of the fiber        bundle 2410;    -   solid angle of incident light on a set of fibers of the fiber        bundle 2410;    -   a cross-sectional diameter or width of the incident light;    -   an incident angle of the incident light on the subject 170        relative to an axis perpendicular to skin of the subject 170        where the incident light interfaces to the subject 170;    -   focusing of the incident light; and/or    -   depth of focus of the incident light on the subject 170.

Several examples are provided, infra, to further illustrate the use ofthe system controller 180 to control shape, position, and/or angle ofthe incident light 2311 reaching a fiber optic bundle, skin of thesubject 170, and/or an element of the photon transport system 120.

Referring again to FIG. 26A, an example is provided of light directed bythe photon transport system 120 from the source system 110 to thesubject directly, through one or more fiber optic of the fiber opticbundle 2410, and/or through the photon transport system 120. However,orientation of the mirror 2610 is varied as a function of time relativeto an incident set of photons pathway. For example, the mirror 2610 istranslated along the x-axis of the mean optical path, is rotated aboutthe y-axis of the mean optical path, and/or is rotated about the z-axisof the mean optical path of the analyzer 100. For example, a firstmirror movement element 2622, such as a first spring or piezoelectricdevice, and a second mirror movement element 2624, such as a secondspring, combine to rotate the mirror about a first axis, such as they-axis as illustrated. Similarly, a third mirror movement element 2626,such as a third spring, and a fourth mirror movement element 2628, suchas a fourth spring, combine to rotate the mirror about a second axis,such as the z-axis as illustrated, in the second time position, t₂,relative to a first time position, t₁.

Referring now to FIG. 26B, an example of the dynamically positionedoptic system 2600 directing the incident light 2311 to a plurality ofpositions as a function of time is provided. As illustrated, the mirror2610 directs light to the light input end 2312 of the fiber bundle 2310.Particularly, the incident light 2311 is directed at a first time, 6, toa first fiber optic 2351 and the incident light 2311 is directed at asecond time, t₂, to a second fiber optic 2352 of a set of fiber optics2350. However, more generally, the dynamically positioned optic system2600 directs the incident light using the mirror 2600 to any y-, z-axisposition along the x-axis of the incident light as a function of time,such as to any optic and/or to a controlled position of skin of thesubject 170.

Referring now to FIG. 26C, an example of the dynamically positionedoptic system 2300 directing the incident light to a plurality ofpositions with a controllable and varying as a function of time solidangle is provided. Optionally, the solid angle is fixed as a function oftime and the position of the incident light 2311 onto the light inputend 2312 of the fiber bundle 2310 is varied as a function of time. Asillustrated, the mirror 2610 directs light to the light input end 2312of the fiber bundle 2310 where the fiber bundle 2310 includes one ormore bundlets, such as the set of fiber optic bundlets 2410. In thisexample, the incident light incident light is directed at a first time6, with a first solid angle to a first fiber optic bunch or group, suchas the first bundlet 2411, described supra, and at a second time, t₂,with a second solid angle to a second fiber optic bunch, such as thesecond bundlet 2412, described supra. In one case, the first solid angleand second solid angle do not overlap, such as at the fiber opticinterface. In another case, the first solid angle and the second solidangle overlap by less than 20, 40, 60, or 80 percent. However, moregenerally, the dynamically positioned optic system 2600 directs theincident light to any y-, z-axis position along the x-axis of theincident light as a function of time at any solid angle or with anyfocusing angle, such as to any optic, any group of optics, and/or to acontrolled position and/or size of skin of the subject 170 relative to adetection zone.

Referring now to FIG. 26D, an example is provided of the dynamicallypositioned optic system 2600 directing the incident light to a pluralityof positions with a varying incident angle onto skin of the subject 170.As illustrated, the mirror 2610 directs light directly to the subject170 without an optic touching the subject 170 or without touching acoupling fluid on the subject 170. However, alternatively the light isredirected after the mirror 2610, such as with a grins lens on a fiberoptic element of the fiber optic bundle 2310. In this example, theincident light is directed at a first time, t₁, with a first incidentangle, θ₁, and at a second time, t₂, with a second incident angle, θ₂.However, more generally, the dynamically positioned optic system 2600directs the incident light to any y-, z-axis position along the x-axisof the incident light as a function of time at any solid angle, with anyfocusing depth, and/or an any incident angle, such as to any opticand/or to a controlled position and/or size of skin of the subject 170relative to a detection zone. In this example, the detection zone is avolume of the subject monitored by the photon transport system 120and/or a lens or mirror of the photon transport system 120 asinteracting with the detector system 130 and a detector therein.

Adaptive Subject Measurement

Delivery of the incident light 2311 to the subject 170 is optionallyvaried in time in terms of position, radial position relative to a pointof the skin of the subject 170, solid angle, incident angle, depth offocus, energy, and/or intensity. Herein, without limitation a spatialillumination system is used to illustrate the controlled and variableuse of incident light.

Referring now to FIG. 27A and FIG. 27B, examples of use of a spatialillumination system 2700 are illustrated for a first subject 171 and asecond subject 172. However, while the examples provided in this sectionuse a fiber optic bundle to illustrate radially controlled irradiationof the sample, the examples are also illustrative of use of thedynamically positioned optic system 2600 for directing incident light toa radially changing position about a collection zone. Still moregenerally the photon transport system 120 in FIGS. 27A and 27B is usedin any spatially resolved system and/or in any time resolved system todeliver photons as a function of radial distance to a detector and/or toa detection zone.

Referring now to FIG. 27A and FIG. 25, an example of application of thespatial illumination system 2400 to the first subject 171 is provided.At a first point in time, the first position, p₁, 2421 of the filterwheel 2430 is aligned with the light input end 2312 of the fiber bundle2310, which results in the light from the first bundlet 2411, whichcorresponds to the first ring 2341, irradiating the sample site 178 at afirst radial distance, r₁, and a first depth, d₁, which as illustratedin FIG. 24A has a mean optical path through the epidermis. Similarly, ata second point in time, the filter wheel 2430 at the second position2422 passes light to the second bundlet 2412, which corresponds to thesecond ring, irradiating the sample site 178 at a second increaseddistance and a second increased depth, which as illustrated in FIG. 27Ahas a mean optical path through the epidermis and dermis. Thedynamically positioned optic system 2600 is optionally used to directlight as a function of time to the first position 2421 and subsequentlyto the second position 2422. Similarly, results of interrogation of thesubject 170 with light passed through the six illustrative fiberillumination rings in FIG. 24A is provided in Table 3. The results ofTable 3 demonstrate that for the first individual, the primeillumination rings for a blood analyte concentration determination arerings two through four as the first ring, sampling the epidermis, doesnot sample the blood filled dermis layer; rings two through four probethe blood filled dermis layer; and rings five and six penetrate throughthe dermis into the subcutaneous fat where photons are lost and theresultant signal-to-noise ratio for the blood analyte decreases.

TABLE 3 Subject 1 Illumination Deepest Tissue Layer Ring Probed 1Epidermis 2 Dermis 3 Dermis 4 Dermis 5 Subcutaneous Fat 6 SubcutaneousFat

Referring now to FIG. 27B and FIG. 24A, an example of application of thespatial illumination system 2400 to the second subject 172 is provided.Again, the dynamically positioned optic system 2600 is optionally usedto deliver light to the spatial illumination system 2400. Results ofinterrogation of the subject 170 with light passed through the sixillustrative fiber illumination rings in FIG. 24A is provided in Table4. For the second subject, it is noted that interrogation of the samplewith the fifth radial fiber ring, f₅, results in a mean optical paththrough the epidermis and dermis, but not through the subcutaneous fat.In stark contrast, the mean optical path using the fifth radial fiberring, f₅, for the second subject 172 has a deepest penetration depthinto the dermis 174. Hence, the fifth radial fiber ring, f₅, yieldsphotons probing the subcutaneous fat 176 for the first subject 171 andyields photons probing the dermis 174 of the second subject 172. Hence,for a water soluble analyte and/or a blood borne analyte, such asglucose, the analyzer 100 is more optimally configured to not use boththe fifth fiber ring, f₅, and the sixth fiber ring, f₆, for the firstsubject 171. However, analyzer 100 is more optimally configured to notuse only the sixth fiber ring, f₆, for the second subject 172, asdescribed infra.

TABLE 4 Subject 2 Illumination Deepest Tissue Layer Ring Probed 1Epidermis 2 Dermis 3 Dermis 4 Dermis 5 Dermis 6 Subcutaneous Fat

In yet another example, light is delivered with known radial distance tothe detection zone, such as with optics of the analyzer, without use ofa fiber optic bundle and/or without the use of a filter wheel. Just asthe illumination ring determines the deepest tissue layer probed,control of the irradiation zone/detection zone distance determines thedeepest tissue layer probed.

Incident Light Control

Referring again to FIGS. 26A-D, the dynamically positioned optic system2600 is optionally used as a function of time to control one or more of:

-   -   delivery of the incident light 2311 to a single selected fiber        optic of the fiber optic bundle 2310;    -   delivery of the incident light 2311 to a selected bundlet of the        set of fiber optic bundlets 2410, such as to the first bundlet        2411 at a first point in time and to the second bundlet 2412 at        a second point in time;    -   variation of solid angle of the incident light 2311 to an optic        and/or to the subject 170;    -   variation of radial position of delivery of the incident light        2311 relative to a fixed location, such as a center of an optic,        a target point on skin of the subject 170, or a center of the        sample site 178;    -   incident angle of the incident light 2311 relative to a plane        tangential to the skin of the subject 170 and/or an axis normal        to the skin of the subject 170 at the sample site 178;    -   apparent focus depth of the incident light 2311 into the skin of        the subject 170;    -   energy; and    -   intensity, such as number of photon per second varying from one        point in time to another by greater than 1, 10, 50, 100, 500,        1000, or 5000 percent.

Time Resolved Spectroscopy

In still yet another example, referring again to time resolvedspectroscopy, instead of delivering light through the filter wheel toforce radial distance, photons are optionally delivered to the skin andthe time resolved gating system is used to determine probably photonpenetration depth. For example, Table 5 shows that at greater elapsedtime to the n^(th) gated detection period, the probability of thedeepest penetration depth reaching deeper tissue layers increases.

TABLE 5 Time Resolved Spectroscopy Elapsed Time Deepest Tissue Layer(picoseconds) Probed 1 Epidermis 10 Dermis 50 Dermis 100 SubcutaneousFat

Data Processing

Referring now to FIG. 28, the data processing system 140 is furtherdescribed. The data processing system 140 optionally uses a step ofpost-processing 2820 to process a set of collected data 2810. Thepost-processing step 2420 optionally operates on data collected as afunction of any of: radial distance of the incident light 2311 to areference point, such as a detector; solid angle of the incident light2311 relative to the subject 170; angle of the incident light 2311relative to skin of the subject 170; and/or depth of focus of theincident light 2311 relative to a surface of the skin of the subject170.

Two-Phase Measurement(s)

Referring now to FIG. 29, in another embodiment, the analyzer 100 isused in two phase system 2900: (1) a sample mapping phase 2910, such asa subject or group mapping phase and (2) a subject specific datacollection phase 2930/data analysis phase. In one example, in the firstmapping phase 2910, skin of the subject 170 is analyzed with theanalyzer 100 using a first optical configuration. Subsequently, themapping phase spectra are analyzed 2920. In the second subject specificdata collection phase 2930, the analyzer 100 is setup in a secondoptical configuration based upon data collected in the sample mappingphase 2910. The second optical configuration is preferably configured toenhance performance of the analyzer 100 in terms of accuracy and/orprecision of estimation and/or determination of an analyte property,such as a noninvasive glucose concentration. Examples provided, infra,use a single subject 170. However, more generally the sample mappingphase 2910 is optionally used to classify the subject into a group orcluster and the analyzer 100 is subsequently setup in a second opticalconfiguration for the group or cluster, which represents a subset of thehuman population, such as by gender, age, skin thickness, waterabsorbance, fat absorbance, protein absorbance, epidermal thickness,dermal thickness, depth of a subcutaneous fat layer, and/or a model fitparameter. For clarity of presentation, several examples are provided,infra, describing use of a sample mapping phase 2910 and a subsequentsubject specific data collection phase 2930.

In a first example, referring again to FIG. 27A and FIG. 27B, a firstoptional two-phase measurement approach is herein described. Optionally,during the first sample mapping phase 2910, the photon transport system120 provides interrogation photons to a particular test subject atcontrolled, but varying, radial distances from the detection system 130.One or more spectral markers, or an algorithmic/mathematicalrepresentation thereof, are used to determine the radial illuminationdistances best used for the particular test subject. An output of thefirst phase is the data processing system 140 selecting how toilluminate/irradiate the subject 170. Subsequently, during the secondsubject specific data collection phase 130, the system controller 180controls the photon transport system 120 to deliver photons overselected conditions and/or optical configuration to the subject 170.

In a second example, a first spectral marker is optionally related tothe absorbance of the subcutaneous fat 176 for the first subject 171.During the first sample mapping phase 2710, the fifth and sixth radialpositions of the fiber probe illustrated in FIG. 24A, yield collectedsignals for the first subject 171 that contain larger than average fatabsorbance features, which indicates that the fifth and sixth fiberrings of the example fiber bundle should not be used in the subsequentsecond data collection phase, which more generally establishes an outerradial distance for subsequent illumination. Still in the first samplemapping phase 130, probing the tissue of the subject with photons fromthe fourth fiber ring yields a reduced signal for the first spectralmarker and/or a larger relative signal for a second spectral markerrelated to the dermis 174, such as a protein absorbance band or analgorithmic/mathematical representation thereof. Hence, the dataprocessing system 140 yields a result that the fifth and sixth radialfiber optic rings or distance of the fiber bundle 170 should not be usedin the second subject specific data collection phase 2930 and that thefourth radial fiber optic ring or distance should be used in the secondsubject specific data collection phase 2930. Subsequently, in the secondsubject specific data collection phase 2930, data collection for analytedetermination ensues using the first through fourth radial positions ofthe fiber bundle, which yields a larger signal-to-noise ratio for dermisconstituents, such as glucose, compared to the use of all six radialpositions of the fiber bundle. Optionally, data already collected in themapping phase is subsequently re-used in the data analysis phase.

In a third example, the first sample mapping phase 2910 of the previousexample is repeated for the second subject 172. The first sample mappingphase 2910 indicates that for the second subject, the sixth radialillumination ring of the fiber bundle illustrated in FIG. 24A should notbe used, but that the fourth and fifth radial illumination ring shouldbe used.

In a fourth example, the first mapping phase 2910 determines positionson the skin where papillary dermis ridges are closest to the skinsurface and positions on the skin where the papillary dermis valleys arefurthest from the skin surface. In the subsequent subject specific datacollection phase 2930, the incident light is optionally targeted at thepapillary dermis valleys, such as greater than 50, 60, or 70 percent ofthe incident light is targeted at the papillary dermis valley and lessthan 30, 40, or 50 percent of the incident light is targeted at thepapillary dermis ridge. The increased percentage of the incident lightstriking the papillary dermis valley increases the number of photonssampling the underlying dermis layer, where blood borne analytes reside,which increases the signal-to-noise ratio of collected data and lowersresultant errors in blood borne analyte property determination.

Generally, a particular subject is optionally probed in a sample mappingphase 2910 and results from the sample mapping phase 2910 are optionallyused to configure analyzer parameters in a subsequent subject specificdata collection phase 2930. While for clarity of presentation, andwithout loss of generality, radial distance was varied in the providedexamples, any optical parameter of the analyzer is optionally varied inthe sample mapping phase 2910, such as sample probe position, incidentlight solid angle, incident light angle, focal length of an optic,position of an optic, energy of incident light, and/or intensity ofincident light. Optionally, the sample mapping phase 2910 and samplespecific data collection phase 2930 occur within less than 1, 5, 10, 20,or 30 seconds of each other. Optionally, the subject 170 does not moveaway from the sample interface 150 between the sample mapping phase 2910and the subject specific data collection phase 130. Further, generallyeach of the spatial and temporal methods yield information onpathlength, b, and/or a product of the molar absorptivity andpathlength, which is not achieved using a standard spectrometer.

In yet another embodiment, the sample interface tip 2316 of the fiberoptic bundle 2310 includes optics that change the mean incident lightangle of individual fibers of the fiber optic bundle 2316 as they firsthit the subject 170. For example, a first optic at the end of a fiber inthe first ring 1041 aims light away from the collection fiber optic2318; a second optic at the end of a fiber in the second ring 2342 aimslight nominally straight into the sample; and a third optic at the endof a fiber in the third ring 2342 aims light toward the collection fiber2318. Generally, the mean direction of the incident light varies bygreater than 5, 10, 15, 20, or 25 degrees.

In still another embodiment, the two-dimensional detector array is usedin the mapping phase to determine positions of best signal and/orpositions of interference, such as a hair follicle. In the data analysisphase, the determined sub-optimal regions, such as those related to thedetected hair follicle, are not used in the analyte determination phase.

Data Processing System

The data processing system 140 is further described herein. Generally,the data processing system uses an instrument configuration analysissystem 2940 to determine an optical configuration of the analyzer 100and/or a software configuration of the analyzer 100 while the sampleproperty analysis system 2950 is used to determine a chemical, aphysical, and/or a medical property, such as an analyte concentration,measured or represented by collected spectra. Further, the dataprocessing system 140 optionally uses a preprocessing step and aprocessing step to determine an instrument configuration and/or todetermine an analyte property.

In one embodiment, the data processing system 140 uses a preprocessingstep to achieve any of: lower noise and/or higher signal. Representativeand non-limiting forms of preprocessing include any of: use of a digitalfilter, use of a convolution function, use of a derivative, use of asmoothing function, use of a resampling algorithm, and/or a form ofassigning one or more spectra to a cluster of a whole. The dataprocessing system subsequently uses any multivariate technique, such asa form of principal components regression, a form of partial leastsquares, and/or a form of a neural network to further process thepre-processed data.

In another embodiment, the data processing system 140 and/or the sampleproperty analysis system 2950 operates on spectra collected by theanalyzer 100, such as in the subject specific data collection phase2930, using a first step of defining finite width channels and a secondstep of feature extraction, which are each further described, infra.

Finite Width Channels

In one example, the sample property analysis system 2950 defines aplurality of finite width channels, where the channels relate to changesin an optical parameter, software setting of the analyzer 100, achemical condition, a physical property, a distance, and/or time. Stillfurther, the channels optionally relate to radial distance between theincident light from the analyzer 100 entering skin of the subject 170and detected light exiting the skin of the subject 170 and detected bythe detector system 130, a focal length of an optic, a solid-angle of aphoton beam from the source system 110, an incident angle of light ontoskin of the subject, and/or a software setting, such as control overspectral resolution. For clarity of presentation, the channels aredescribed herein in terms of wavelength channels. For example, aspectrum is collected over a range of wavelengths and the finite widthchannels represent finite width wavelength channels within the spectrum.Generally, the channels are processed to enhance localized signal, todecrease localized noise, and/or are processed using a cross-wavelettransform.

In one case, the sample property analysis system 2950 defines aplurality of finite width wavelength channels, such as more than 3, 5,10, 15, 20, 30, 40, or 50 wavelength channels contained in a broaderspectral region, such as within a spectrum from 900 to 2500 nanometersor within a sub-range therein, such as within 1100 to 1800 nanometers.The plurality of multiple finite width wavelength channels enhanceaccessibility to content related to: (1) a target analyte, such as aglucose concentration, and (2) a measurement context, such as the stateof skin of the subject 170, which is used as information in aself-correcting background.

Feature Extraction

In one case, feature extraction determines and/or calculates coherencebetween channels, which is referred to herein as cross-coherence, toidentify and/or enhance information common to the analytical signal,such as frequency, wavelength, shift, and/or phase information.Subsequently, cross-coherence terms are selected using a metric, such asto provide maximum contrast between: (1) the target analyte or signaland (2) the measurement context or background. Examples of backgroundinclude, but are not limited to: spectral interference, instrument driftimpacting the acquired signal, spectral variation resultant fromphysiology and/or tissue variation, temperature impact on the analyzer,mechanical variations in the analyzer as a function of time, and thelike.

Generally, the cross-coherence terms function to reduce toward or tomonotonicity detected variation as a function of analyte concentration.In a particular instance, an N×N grid is generated per spectrum, whichis symmetric about the diagonal of the N×N grid, with each grid elementrepresenting an M term coherence estimate versus frequency, where N is apositive integer of at least three.

Model

Typically, a model, such as a nonlinear model, is constructed to map theextracted features to the analyte property, such as a glucoseconcentration. For example, the total differential power of thecross-coherence estimate is determined between features related to theanalyte versus the background and a separate nonlinear function iscalculated for multiple analyte ranges.

Absorbance Spectra

The data processing system 140 optionally uses absorbance spectra ofskin and/or blood constituents, such as water absorbance peaks at about1450 nm or in the range of 1350 to 1500 nm.

Personal Communication Device

Herein, a personal communication device comprises any of a wirelessphone, a cell phone, a smart phone, a tablet, a phablet, a wearableinternet connectable accessory, a wearable internet connectable garment,and/or a smart wearable accessory, such as a watch with internet and/orphone communication ability. Optionally, the analyzer 100 has no displayscreen and results are transmitted to a personal communication device ofthe user, which allows a smaller analyzer 100 and/or the analyzer to besemi-continuously worn in a non-conspicuous location, such as under ashirt or around the torso of the individual.

Optionally, the personal communication device and/or the analyzercommunicate with a data processing center. For example, the dataprocessing center received data from the analyzer 100 through use of atleast one wireless step, processes the data, and sends a result and/or amodel parameter to the personal communication device of the user,resulting in one or more of: a displayed analyte concentration, adescription of detection of an analyzer error, and/or an alert, such asa rapidly falling glucose concentration, an abnormally high glucoseconcentration, and/or a request for use of an alternative glucosedetermination method.

Still yet another embodiment includes any combination and/or permutationof any of the analyzer and/or sensor elements described herein.

The particular implementations shown and described are illustrative ofthe invention and its best mode and are not intended to otherwise limitthe scope of the present invention in any way. Indeed, for the sake ofbrevity, conventional manufacturing, connection, preparation, and otherfunctional aspects of the system may not be described in detail.Furthermore, the connecting lines shown in the various figures areintended to represent exemplary functional relationships and/or physicalcouplings between the various elements. Many alternative or additionalfunctional relationships or physical connections may be present in apractical system.

In the foregoing description, the invention has been described withreference to specific exemplary embodiments; however, it will beappreciated that various modifications and changes may be made withoutdeparting from the scope of the present invention as set forth herein.The description and figures are to be regarded in an illustrativemanner, rather than a restrictive one and all such modifications areintended to be included within the scope of the present invention.Accordingly, the scope of the invention should be determined by thegeneric embodiments described herein and their legal equivalents ratherthan by merely the specific examples described above. For example, thesteps recited in any method or process embodiment may be executed in anyorder and are not limited to the explicit order presented in thespecific examples. Additionally, the components and/or elements recitedin any apparatus embodiment may be assembled or otherwise operationallyconfigured in a variety of permutations to produce substantially thesame result as the present invention and are accordingly not limited tothe specific configuration recited in the specific examples.

Benefits, other advantages and solutions to problems have been describedabove with regard to particular embodiments; however, any benefit,advantage, solution to problems or any element that may cause anyparticular benefit, advantage or solution to occur or to become morepronounced are not to be construed as critical, required or essentialfeatures or components.

As used herein, the terms “comprises”, “comprising”, or any variationthereof, are intended to reference a non-exclusive inclusion, such thata process, method, article, composition or apparatus that comprises alist of elements does not include only those elements recited, but mayalso include other elements not expressly listed or inherent to suchprocess, method, article, composition or apparatus. Other combinationsand/or modifications of the above-described structures, arrangements,applications, proportions, elements, materials or components used in thepractice of the present invention, in addition to those not specificallyrecited, may be varied or otherwise particularly adapted to specificenvironments, manufacturing specifications, design parameters or otheroperating requirements without departing from the general principles ofthe same.

Herein, a set of fixed numbers, such as 1, 2, 3, 4, 5, 10, or 20optionally means at least any number in the set of fixed number and/orless than any number in the set of fixed numbers.

Herein, specific wavelengths are used to facilitate communication of keyspectroscopic points. However, the specific wavelengths presented areoptionally plus and/or minus 10, 20, 30, 40, 50, 75, or 100 nm.

Although the invention has been described herein with reference tocertain preferred embodiments, one skilled in the art will readilyappreciate that other applications may be substituted for those setforth herein without departing from the spirit and scope of the presentinvention. Accordingly, the invention should only be limited by theClaims included below.

1. A method for noninvasively determining an analyte concentration of aperson, comprising the steps of: providing a near-infrared analyzer,comprising: at least one near-infrared source; a detector; and a photontransport system configured to direct photons from said source, via asample illumination zone, to said detector via both a detection zone anda face of an analyzer-sample optical interface; dynamically changing,within a time window of data collection for a single analyteconcentration determination, a mean radial illumination position ofincident light from said near-infrared source relative to a center ofthe detection zone of said analyzer-sample optical interface, said stepof dynamically changing further comprising: directing the photons,during a first time period of the time window, to a first arc ofillumination optics at a first range of radial distances from thedetection zone; and directing the photons, during a second time periodof the time window, to a second arc of illumination optics at a secondrange of radial distances from the detection zone, wherein at saidanalyzer-sample optical interface none of said first range of radialdistances overlap any of said second range of radial distances.
 2. Themethod of claim 1, said step of dynamically changing a mean radialillumination position further comprising the steps of: at a first time,directing light from said source to a first optic; and at a second time,directing light from said source to a second optic, said second optic ina distinct optical path not using said first optic.
 3. The method ofclaim 2, further comprising the step of: within the time window forcollection of data for determination of the single analyte concentrationdetermination, changing an effective depth of penetration of theincident light into skin of the person by at least twenty percent. 4.The method of claim 3, further comprising the steps of: at a first time,directing photons from said near-infrared source to a first subset offiber optics in a fiber optic bundle; and at a second time, directingphotons from said near-infrared source to a second subset of fiberoptics in said fiber optic bundle.
 5. The method of claim 4, furthercomprising the step of: using a rotatable and selectable opaqueperimeter aperture to change a cross-sectional diameter of a light beamfrom said near-infrared source by at least twenty-five percent withinthe time window.
 6. (canceled)
 7. (canceled)
 8. The method of claim 1,said step of dynamically changing, within the time window of datacollection for the single analyte concentration determination, the meanradial illumination position of incident light, further comprising thesteps of: at a first point in time, radially directing and positioningthe incident light at a first radial distance from the center of theanalyzer-subject interface yielding a median maximum depth ofpenetration in an epidermis layer of skin of the subject; and at asecond point in time, radially directing and positioning the incidentlight at a second radial distance from the center of theanalyzer-subject interface yielding a mean maximum depth of penetrationin a dermis layer of skin of the subject.
 9. The method of claim 1,further comprising the steps of, during the time window of datacollection for the single analyte concentration determination:generating a subject specific tissue map; and subsequently performingsaid step of dynamically changing a mean radial illumination position ofthe incident light using information from the subject-specific tissuemap.
 10. The method of claim 1, said step of dynamically changing a meanradial illumination position of the incident light further comprisingthe steps of: delivering the incident light proximate at least one of:an edge of a detector array; and a corner of a detector array.
 11. Themethod of claim 1, said step of dynamically changing a mean radialillumination position of the incident light further comprising the stepof: delivering the incident light sequentially to at least four opticalfibers proximate at least one of: an edge of a detector array; and acorner of a detector array.
 12. The method of claim 1, furthercomprising the step of: dynamically changing, within the time window ofdata collection for the single analyte concentration determination, asolid angle of incident light striking the analyzer-tissue interface bygreater than ten percent.
 13. The method of claim 12, said step ofdynamically changing a solid angle further comprising the step of:within the time window, irradiating the subject with two solid angles ofincident light overlapping by less than twenty percent.
 14. An apparatusfor noninvasively determining an analyte concentration of a person,comprising: a near-infrared analyzer, comprising: at least onenear-infrared source; a detector; and a photon transport systemconfigured to direct photons from said source, via a sample illuminationzone, to said detector via both a detection zone and a face of ananalyzer-sample optical interface, said photon transport system furthercomprising: means for dynamically changing, within a time period of datacollection for a single analyte concentration determination, a radialillumination position of incident light from said near-infrared sourcerelative to a center of the detection zone of said analyzer-sampleoptical interface, said means for dynamically changing the radialillumination position comprising a dynamically positioned optic system;a first arc of illumination optics configured to direct the photons,during a first time period of the time window, to a first range ofradial distances from the detection zone; and a second arc ofillumination optics configured to direct the photons, during a secondtime period of the time window, to a second range of radial distancesfrom the detection zone, wherein at said analyzer-sample opticalinterface none of said first range of radial distances overlap than anyof said second range of radial distances.
 15. (canceled)
 16. Theapparatus of claim 14, said means for dynamically changing the radialposition of the incident light, comprising: an electromechanicallydirected mask wheel.
 17. The apparatus of claim 16, said detectorfurther comprising: a two-dimensional detector array comprising at leastsix, electrically connected in series, detector elements along an arc ofat least forty-five degrees.
 18. The apparatus of claim 14, said meansfor dynamically changing the radial position of the incident lightcomprising an array of light emitting diodes at least eighty percentcircumferentially surrounded by said detector at the analyzer-sampleoptical interface, said detector comprising at least one detector array.19. The apparatus of claim 14, said photon transport system furthercomprising: at least one fiber optic terminating at said analyzer-sampleinterface at a third radial distance from the detection zone of saidanalyzer-sample optical interface, said third radial distance bothlarger than said first radial distance and smaller than said secondradial distance.
 20. The method of claim 1, further comprising the stepof: directing the photons to a third range of radial distances from thedetection zone at said analyzer-sample optical interface, during a thirdtime period of the time window, using a third arc of illuminationoptics, said third range of radial distances overlapping at least someof said first range of radial distances.